HU207088B - Process for producing 3-propenylcefem derivatives and pharmaceutical compositions comprising such compounds - Google Patents

Abstract

A 3-propenylcephem derivative of the following formula: wherein R₁ represents a fluoro-substituted lower alkyl group or a cyano-substituted lower alkyl group, and A represents a cyclic or an acylic ammonio group, or a pharmaceutically acceptable salt thereof. exhibiting excellent anti-bacterial activities against both Gram-positive bacteria and Gram-negative bactena; Process for the preparation thereof; Anti-bacterial composition; Intermediate for the 3-propenylcehem derivative; and Process for the preparation of the intermediate.

Description

The present invention relates to novel 3-propenyl cephem derivatives having antibacterial activity and to pharmaceutical compositions containing such compounds.

Cephem derivatives containing the ammonium group are known from Japanese Publication No. 174387/83; 198490/83;

130295/84; 172493/84; 219292/84; 97983/85;

197693/85: 5084/86.

Particularly similar compounds to those of the present invention are described in Japanese Publication Nos. 172,493/84 and 5084/86.

We have found that cephem derivatives containing a 3-position ammoniumpropenyl group and a 7-position lower alkoxyimino group or a cyano-substituted lower alkoxyimino group at the 7-position of the side chain have very good antibacterial properties. agents. SUMMARY OF THE INVENTION It is an object of the present invention to provide a process for the preparation of these novel cephem derivatives and pharmaceutical compositions containing such compounds. The invention also relates to processes for the preparation of intermediates of the above compounds.

The process of the present invention provides 3-propenyl cephem derivatives of formula (I) and pharmaceutically acceptable salts thereof. In the general formula (I)

R 1 is fluoro lower alkyl or cyano lower alkyl,

A is a group of formula (a ') wherein

R ₂ , R ₃ and R ₄ are each independently lower alkyl, hydroxy lower alkyl, carbamoyl lower alkyl, amino, (lower alkyl) carbonylamino lower alkyl, amino-; sulfonylaminocarbonyl lower alkyl, (lower alkyl) sulfonylaminocarbonyl lower alkyl, (lower alkyl) aminocarbonyl lower alkyl, (hydroxyl) (carbonyl) lower alkyl-; , hydroxy and hydroxy (lower alkyl) aminocarbonyl lower alkyl, (lower alkyloxy) aminocarbonyl lower alkyl, hydroxyaminocarbonyl lower alkyl, amino- carbonyl (lower alkyl) aminocarbonyl lower alkyl, (lower alkyl) amino lower alkyl, carboxylate (lower alkyl) di- (lower alkyl) ammonium lower alkyl, cyano-short alkyl; d i- (lower alkyl) amino-lower alkyl, (lower alkyl) amino and hydroxyl lower alkyl, urea, hydroxy, carboxyl lower alkyl, (hydroxyl) (carbamoyl) lower alkyl, lower alkyloxy-lower alkyl, di- (lower alkyl) aminocarbonyl-lower alkyl, dicarbamoyl-lower alkyl, bis / hydroxy (lower alkyl) / aminocarbonyl-lower alkyl, dihydroxy-lower alkyl, trihydroxy-lower alkyl, bis / hydroxy (lower alkyl) amino-lower alkyl, amino-lower alkyl, oxo-lower alkyl- , di- (lower alkylimino-lower alkyl, 5-membered heterocyclic lower alkyl, wherein the heterocyclic group is pyrazolylimidazolyl, oxadiazolyl or tetrazolyl), and

A may also be a group of formulas (a) to (r) in which

R ₅ is lower alkyl, carbamoyl lower alkyl, amino lower alkyl, hydroxyl lower alkyl, carboxyl lower alkyl, cyano lower alkyl, dihydroxy lower alkyl or carbamido lower alkyl, and the above groups (a) - (r) may be substituted on the ring with one or more of the following: hydroxy lower alkyl, hydroxyl, formylsulfone, carboxyl lower alkyl- , carbamoyl, sulfamoyl, carboxyl, hydroxyimino-lower alkyl, imino-lower alkyl, bis / hydroxy (lower alkyl) aminocarbonyl, hydroxy (lower alkyl) aminocarbonyl , amino, morpho-carbonyl, carboxy (lower alkyloxy) lower alkyl, carboxy (lower alkyl thio) and lower alkyl, and sulfone lower alkyl.

For the purposes of Rj, lower alkyl substituted by fluoro is, for example, fluoromethyl, difluoromethyl, 2-fluoroethyl, 2,2-difluoroethyl, 2,2,2-trifluoroethyl-. 1-fluoroethyl, 2-fluoro-propyl, 1-fluoro-methyl-2-fluoro-ethyl, 3-fluoro-propyl, preferably fluoro-methyl.

Examples of lower alkyl groups substituted with a cyano group in R 1 include cyanomethyl, 2-cyanoethyl, 3-cyanopropyl.

Lower alkyl is C 1-4 alkyl such as methyl, ethyl, npropyl, i-propyl, η-butyl, i-butyl, sec-butyl and tert-butyl.

Non-toxic pharmaceutically acceptable salts of the compounds of formula (I) include, for example: an alkali metal such as sodium or potassium, ammonium, quaternary ammonium such as tetraethylammonium or beta, an alkaline earth metal such as calcium; or magnesium salts; and salts with inorganic acids such as hydrochlorides, hydrobromides, hydroiodides, sulfates, carbonates or bicarbonates; organic carboxylates such as acetates, maleates, lactates or tartrates, organic sulfonates such as methanesulfonates, hydroxymethane sulfonates, hydroxyethane sulfonates, taurine

I

Salts, benzenesulfonates or toluenesulfonates; amino acid salts such as arginine, lysine. serine salts, and also aspartates or glutamates; amino salts such as trimethylamine, triethylamine, pyridine, procaine, picoline, dicyclohexylamine, Ν, Ν'-dibenzylethylenediamine, N-methylglucaine. diethanolamine. salts of triethanolamine, tris (hydroxy-octylamino) -etetane or phenethylbenzylamine.

The compounds of formula (I) also exist in the form of color isomers (Z) and anti-isomers (E), depending on the different configurations of group (a). Although both isomers are within the scope of the invention, the color isomers are more favorable due to their antibacterial activity.

The compounds of formula (I) are prepared by the process of the invention by reacting a compound of formula (II), wherein R1 is a lower alkyl or a cyano lower alkyl substituted by a fluorine atom, X is a halogen atom, and The carboxyl group of the compound may also be protected or the salt of the compound of formula (11) may be reacted with a compound of formula (III) wherein A 'is an amine of group A and wherein the functional groups may also be protected. Salts of the compounds of formula (III) may also be used in the reaction and, if necessary, deprotected at the end of the reaction.

In the compounds of formula (II) above, X is preferably iodine, bromine or chlorine.

The above reaction is carried out at a temperature of -10 to 60 ° C, preferably 0 to 40 ° C, optionally in anhydrous saline solvent. Organic solvents that may be used include, for example, lower alkyl nitriles such as acetonitrile or propionitrile; halogenated lower alkanes such as chloromethane, dichloromethane or chloroform; ethers such as tetrahydrofuran, dioxane or ethyl ether; amides such as dimethylformamide; esters such as ethyl acetate; ketones such as acetone; hydrocarbons such as benzene; alcohols such as methanol or ethanol; sulfoxides such as dimethyl sulfoxides or a mixture of the above solvents.

Deprotection may be carried out according to known procedures, depending on the nature of the protecting group, such as hydrolysis or reduction.

The salts and protected forms of the compounds of formula (II) and (III) may be used in any variant as long as the above reaction is not adversely affected.

Examples of protecting groups which may be used are: amino function groups: l'ormyl-. acetyl, chloroacetyl, dichloroacetyl. phenylacetyl. lienylacetyl, t-butoxycarbonyl. benzyloxycarbonyl, trityl, p-methoxybenzyl, diphenylmethyl, benzylidene, p-nitrobenzylidene and m-chlorobenzylidene; carboxyl protecting groups: p-methoxybenzyl, p-nitrobenzyl, t-butyl, methyl, 2,2,2-trichloroethyl, diphenylmethyl and pivaloyloxymethyl. A silylating agent, such as one of the following, is preferably used because the silylation can simultaneously protect both the amino and carboxyl groups: N, O-bis (trimethylsilyl) acetamide, N-methyl-N- (trimethylsilyl) acetamide, N-methyl-N- (trimethylsilyl) trifluoroacetamide, or N- (trimethylsilyl) acetamide.

Salts of the compounds of formula (II) and (III) include, for example: an alkali metal such as sodium or potassium; an alkaline earth metal such as calcium or magnesium; ammonium, quaternary ammonium such as triethylammonium or beta; hydrochlorides, hydrobromides, sulfates, carbonates, hydroiodides or bicarbonates; organic carboxylates such as acetates, trifluoroacetates, maleates, lactates or tartrates; organic sulfonates, such as methane sulfonates, hydroxymethane sulfonates, hydroxyethane sulfonates, taurine, benzene sulfonates, or toluene sulfonates; an amine such as trimethylamine, triethylamine. pyridine, procaine, picoline, dicyclohexylamine, Ν, Ν'-dibenzyl-ethylenediamine, N-methylglucamine, diethanolamine. trictanolamine, tris (hydroxymethylamino) methane or phenethylbenzylamine; salts of amino acids such as arginine, aspartate, lysine, glutamate, serine or glycine.

The compounds of general formula (I) according to the invention have very strong antibacterial activity against Gram-positive and Gram-negative bacteria and are thus useful in the treatment of bacterial infections and diseases.

The compounds of the present invention may be used alone or in the form of their formulations, preferably in the form of injection formulations. Juk their daily dose is usually between 100 mg and 10 g, given in 1-4 divided doses per day for intravenous or intramuscular administration. Of course, these dosages may be varied depending on the age of the patients and the type of disease.

Formulations for injection are prepared in a known manner, for example by dissolving the appropriate active ingredient in distilled water, if necessary in the presence of an isotonic agent, solution mediator and / or other excipient. Alternatively, it may be filled into a suitable vial in powder form and blended immediately before use. For these formulations, the solution is dissolved in distilled water, physiological saline, glucose solution or amino acid infusion solution before use.

The starting compounds of formula (II), the protected forms and the salts thereof, are novel compounds. These compounds may be prepared by reacting a compound of Formula IV, wherein R 1 is as defined above, or a reactive derivative thereof, or a protected derivative or salt thereof, with a compound of Formula V, wherein X is as defined above, or a protected form or salt thereof. and optionally deprotecting and / or replacing the halogen with another halogen.

The above reaction is carried out according to the parameters of known N-acylation reactions. For example, the reaction is -50 3

The reaction is carried out at a temperature of + 50 ° C in an inert solvent such as tetrahydrofuran, ethyl acetate, acetone, Ν, Ν-dimethylformamide, acetonitrile, dioxane or a mixture thereof.

The reactive derivative of the compound of formula (IV) may be, for example, an acid halide. For example, acid chloride or acid bromide, symmetric acid anhydride, mixed acid anhydride, active ester, active acid or active acid amide.

When the compound of formula (IV) is used in the form of the free acid or its salt, the reaction is preferably a condensing agent. For example, it is carried out in the presence of Ν, Ν'-dicyclohexylcarbodiinide, p-toluenesulfonic acid or the like. Conversion of X halogen to another halogen atom is also carried out according to known procedures. For example, when the compound of formula (II) is X iodine. it is prepared from a compound of formula II. in which X is chlorine. by reacting this compound with an alkali metal iodide.

Compounds of formula (VI) wherein R ₍ ,) is a carboxyl, carbonyl, carbamoyl or cyano group - the water forms and salts of these compounds are also novel compounds.

Suitable amino or carboxy protecting groups for the above chemical compound are those listed above for the compounds of formula II. The following compounds may be prepared according to Scheme A.

Compound (VIII) is prepared by reacting compound (VII) with halofluoromethane in an inert solvent.

For example, if the fluorine methane compound is bromine fluoromethane. iodofluoromethan may be used. The reaction temperature is -30 to 100 ° C.

Compound (IX) is prepared by treating compound (VIII) with a dehydrating agent in an inert solvent. The reaction temperature for this reaction is preferably room temperature, for example, dichloride or phosphorus oxychloride or lionyl chloride.

Compound (X) is prepared by reacting compound (IX) with ammonia and / or ammonium salt in an inert solvent such as water, lower alcohol, acetone or chloroform. The reaction temperature is preferably -20 ° C to room temperature. The ammonium salt is preferably ammonium chloride, ammonium acetate or ammonium sulfate.

The compound of formula XI is prepared as follows. reacting a compound of formula (X) with a halogenating agent such as biogas or chlorine in gaseous form, and then contacting it with an alkali metal lyocyanal, preferably in the presence of a base. The reaction temperature is preferably from -20 ° C to room temperature. Examples of the alkali metal cyanate are potassium tuncyanate or sodium cyanal.

A compound of formula (XII) or a salt thereof in which the amino group is protected is prepared by treating a compound of formula (XI) or a salt thereof in which the amino group is protected with an oxidizing agent in the presence of a base and optionally protecting group. removed. The reaction is carried out at 0 ° C to 70 ° C in water, in the presence of a buffer or in the presence of a previous lower alcohol.

The oxidizing agent used is hydrogen peroxide or oxygen, the base being sodium hydroxide or potassium hydroxide.

A compound of formula (XIII) or a salt thereof in which the amino group is chemically protected is prepared by hydrolyzing a compound of formula (XII) or a salt in which the amino group is protected in the presence of a base and optionally deprotecting.

The base, solvent and reaction conditions used are the same as those described above.

The compound of formula (XIII) or a salt thereof may also be prepared in this manner. to a compound of formula XIV. in which the amino and / or carboxyl groups are protected, is reacted with halofluoromethane and then optionally deprotected. Exemplary halofluoromethanes include bromofluoromelane, iodofluoromelane or chlorofluoromethane. The reaction is carried out in an inene solvent at a temperature of -30 ° C to 100 ° C. Examples of the solvent include sulfoxides such as dimethyl sulfoxide, amides such as Ν, Ν'-dimethylacelamide, formamide, hexamethylsulforyl triamide, ketones such as acetone or a mixture thereof.

The compound of formula (XV) in which the amino group is protected or a salt thereof is formed from a compound of formula (XIII). in which the amino group is protected or may be prepared from a salt thereof by a halogenating agent. Examples of the halogenated cosolvent include lysol oxide, thionyl chloride, thionyl bromide. phosphorus oxychloride. The reaction is carried out in an inert solvent such as dichloromethane, tetrahydrofuran, ethyl acetate, chloroform or a mixture thereof at a temperature of -50 to 50 ° C. The following examples illustrate the process of the invention in more detail.

E! Example 1 (Preparation of starting material)

Elyl 2- (5-Tritylylamino-1,2,4-thiadiazol-3-yl) - (Z) -2-fluoro-moxyloximino-acetate (Compound of Formula I)

60.4 g of ethyl 2- (5-tritylylamino-1,2,4-thiadiazol-3-yl) (Z) -2-hydroxyiminoacetal are dissolved in 210 ml of dimethylsulfoxide, 96.48 g are added. potassium carbonate under ice-cooling. The resulting solution was stirred for 10 minutes. 19 g of bromofluoromethane are added and the resulting solution is stirred at room temperature for 3 hours. Ethyl acetate (1 L) was added, the solution was washed with water and brine, dried (MgSO4), and the solvent was distilled off and 120 mL of ethanol was added to the residue. The precipitated crystalline material was collected by filtration and washed with ethanol to give 58.2 g of the title compound.

HU 207 088 B

Example E2

2- (5-Tritylamino-1,2.4-triadiazol-3-yl) - (Z) -2-fluoromethoxyimino-acetic acid (Compound 2) is winterized in a mixture of water (ml) and ethanol (146 ml).

2.04 g of sodium hydroxide. 17.87 g of the product obtained in the previous Example E1 are added and the resulting solution is stirred at reflux for 20 minutes. The solution was then quenched under reduced pressure, ethyl acetate (200 mL) and 1N hydrochloric acid (77 mL) were added, the ethyl acetate layer was separated, washed with water and brine, dried over anhydrous magnesium sulfate and the solvent was distilled off. The remaining crystalline material was stirred with pelroline and filtered to give 16.55 g of the title compound.

Example E3 p-Methoxybenzyl 7beta- [2- (5-tritylamino-1,2,4-thiadiazol-3-yl) - (Z) -2-fluoromethoxyimino] -amido [3-a] ) -3-Chloro-1-propen-1-yl / -3-cefcm-4-carboxylate (Compound 3)

4.1 ml of tetrahydrofuran and 348 microliters of dimethylformamide were stirred at -10 ° C, 418 microliters of phosphorus oxychloride were added and the resulting mixture was stirred under ice-cooling for 90 minutes. To the solution thus obtained, 1.73 g of E2 (5.5 g) in teirahydrofuran (5.5 ml) was added at -10 ° C and stirred under ice-cooling for 90 minutes. The reaction mixture was then cooled to -20 ° C and 1.78 g of pmethoxybenzyl-7-beta-amino-3 - ((Z) -3-chloro-1-propan-1-yl) -3-cephem-4-carboxylic acid was added. hydrochloride and 2.95 g of N- (trimethylsilyl) acetamide, 18 ml of ethyl acetate and 5.5 ml of tetrahydrofuran and stirring was continued at -10 ° C for 1 hour. To the reaction solution was added ethyl acetate (100 mL), the resulting solution was washed successively with water, saturated aqueous sodium bicarbonate and brine, dried over anhydrous magnesium sulfate, and the solvent was distilled off. The residue was chromatographed on silica gel to give the title compound (2.65 g).

Example E4 p-Methoxybenzyl 7beta- [2- (5-tritylamino-1,2,4-thiadiazol-3-yl- (Z) -2-fluoromethoxyimino-acetamido] -3- (E) - 3-Iodo-1-propen-1-yl / -3-cephem-4-carboxylate (Compound 4)

Dissolve 10.11 g of Example E3 in 212 ml of acetone, add 9.03 g of sodium iodidol under ice-cooling, and stir the resulting solution for 15 minutes under ice-cooling and then at room temperature for a further 90 minutes. The solvent was then distilled off, the residue was extracted with ethyl acetate (500 mL), and the extract was washed with saturated aqueous sodium thiosulfate solution and brine, dried over anhydrous magnesium sulfate, and the extract was concentrated under reduced pressure. The precipitated material was collected by filtration to give the title product (10.92 g).

Example E5 p-Methoxybenzyl 7beta- [2- (5-tritylamino-1,2,4-thiazolazol-3-yl) - (Z) -yl] -chloromethoxyimino-acetamido] -3 - [(Z) - 3-Chloro-1-propynyl-3-cephem-4-carboxylate (Compound 5)

In the same manner as in Example E3, 2 g of 2- (5-tritylamino-1,2.4-thiadiazol-3-yl) - (Z) -2-difluoromethoxyiminoacetic acid were added to 1795 g of p-methoxybenzyl 7-beta-amino-3- (Z) 3-chloro-1-propan-1-yl] -3-celem-4-carboxylate hydrochloride to give 3.17 g of the title compound.

Example E6 p-Methoxybenzyl 7beta- [2- (5-litrylamino-1,2,4-thiadiazol-3-yl) - (Z) -2-difluoromethoxyiminoacetamido] -3- (E). ) -3-Iodo-1-propen-1-yl / -3-cephem-4-carboxylate (Compound 6)

Following the procedure described in Example E4, 3 g of the compound prepared in Example E5 are reacted with 2.62 g of sodium iodide to give 2.92 g of the title compound.

/. example

7beta- (2- (5-Amino-1,2,4-thiadiazol-3-yl) - (Z) -2-fluoromethoxyiminoacetamido) -3- (E) -3- (carbamoylmethyl) -ethyl-methyl-ammonium) -1-propen-1-yl / -3-cephem-4-carboxylate (compound 7)

550 mg of the compound obtained in Example E4 are dissolved in a mixture of 20 ml of ethyl acetate and 10 ml of ethyl ether, 117 mg of ethyl methylacetamide are added, the solution is stirred at room temperature for 4 hours and 30 minutes, and isopropyl ether is added. the precipitate was collected by filtration and dried. This gives 400 mg of a tan powder,

The powder thus obtained was mixed with 4.5 ml of trifluoroacetic acid and 4 ml of anisole and stirred for 1 hour under ice-cooling, followed by addition of ethyl ether. The precipitate was filtered off, washed with ethyl ether and suspended in water (5 ml). the suspension is adjusted to pH 5.5-6.5 with sodium acetate, the insoluble material is filtered off, and the filtrate is purified by reverse phase chromatography to give 49 mg of the title compound.

Example 2

7béta- / 2- (5-amino-l, 2,4-thiadiazol-3-yl) - (Z) -2-fluoro-methoxy-acetamido / 3 - / (E) -3- / l (2-Hydroxy-1-yl) -4-carbamoyl-1-piperidin-1-propen-1-yl / 3-acyl-4-carboxylate (Compound 8)

700 mg of the compound obtained in Example E4 are dissolved in 3 ml of dyninyl formamide, 194 mg of 1- (2-hydroxyethyl) isonipckolamidol in 0.5 ml of dimethyl 1-formamide are added, and the resulting solution is stirred overnight. Ethyl ether (120 mL) was added to the reaction solution and the precipitated precipitate was filtered to give 680 mg of a yellow powder.

The above powder was mixed with 4.5 ml of anisole, 5.3 ml of trifluoroacetic acid was added dropwise over 30 minutes with stirring and ice cooling, and the resulting mixture was stirred for an additional 1.5 hours. To the reaction mixture is added 50 ml of isopropyl ether, the precipitate is filtered off, the precipitate is suspended in 30 ml of water and the suspension is adjusted to pH 7.0 with sodium acetate. Λ The remaining insoluble material is filtered off and the filtrate is purified by reverse phase chromatography on silica gel to give the following two isomers:

2-1 isomer 21 mg

2- 2 isomers 20 mg

A 1: 1 mixture of the two isomers is 50 mg.

Example 3

7β- (2- (5-Amino-1,2,4-thiadiazol-3-yl) - (Z) -2-fluoromethoxyaminoacetamido) -3- (E) -3- (1S- (Carbamoyl-ethyl) -dimethyl-ammonio-1-propan-1-yl / -3-cephem-4-carboxylate (Compound 3-1.9) 7beta- (2- (5-Amino-1,2) , 4-Thiadiazol-3-yl) - (Z'-2-phthalomethoxyiminoacetamido) -3- (E) -3- (1R-carbamoyl-ethyl) -dimethylammonium - 1-Propan-1-yl] -3-cephem-4-carboxylate (3-2,10)

600 mg of the compound obtained in Example E4 are dissolved in a mixture of ml of ethyl acetate and 10 ml of ethyl ether. 150 mg of 2-dimethylaminopropylamide are added and the resulting mixture is stirred for 3 hours at room temperature. Isopropyl ether was added and the precipitate was collected and dried to give 50 mg of a tan solid.

This material was mixed with a mixture of 5.5 ml of trifluoroacetate and 5 ml of anisole. After stirring for 1 hour under ice-cold, it was added with ethyl acetate. The precipitate was filtered off, washed with ethyl ether, suspended in water (5 ml) and adjusted to pH 5.5-6.5 with sodium acellate. The insoluble material was removed by filtration and the filtrate was purified by reverse phase chromatography on silica gel (8 mg).

3- (1), 7 mg of 3-2 and 4 mg of a mixture of 3-1 and 3-2 (1: 1) were obtained.

Example 4

7béta- / 2- (5-amino-l, 2,4-thiadiazol-3-yl) - (Z) -2-fluoro-methoxyimino acetamido / 3 - / (E) -3 - / (2 -hydroxypropyl) dimethylammonio-1-propan-1-yl / -3-ce1'em4-carboxylate (compound of formula 11)

550 mg of the compound obtained in Example E4 are dissolved in a mixture of 20 ml of ethyl acetate and 10 ml of ethyl ether. 0.124 mL of 3-dimethylamino-2-propanol was added. the resulting solution was stirred at room temperature for 1.5 hours, then isopropanol was added and the precipitate which was filtered off and dried. This gave 530 mg of a tan powder.

The above powder was mixed with a mixture of 5.5 ml of trifluoroacetic acid and 5 ml of anisole under ice-cooling for 1 hour and then ethyl acetate. The precipitate was filtered off, washed with ethyl ether and suspended in water (5 mL). The suspension is adjusted to pH 5.5-6.5 with sodium acetate, the insoluble material is filtered off and the filtrate is purified by reverse phase chromatography on silica gel. 70 mg of the title compound are obtained.

Example 5

7bα-2- (5-amino-1,2,4-thiadiazol-3-yl) - (Z) -2-fluoromethoxyiminoacetamide; (1R-Carbamoyl-2-hydroxyethyl) -dimethylammonio-1-propenyl-3-cephem-4-carboxylate (Compound 12) g of Example E4 was dissolved in 2 ml of dimethylformamide. and then, under ice-cooling, a solution of N, N-dimethylserinamide prepared as described. After dissolving 590 mg of N, N-dimethyl-D-serinanide trifluoroacetate in 5 ml of methanol, 2.4 ml of aqueous sodium hydroxide was added, the solvent was distilled off under reduced pressure and the residue was extracted with 2 ml of acetonitrile. The combined solutions were stirred for 30 minutes, ethyl ether was added and the precipitate was collected by filtration to give 1.1 g of a yellow powder.

This powder was mixed with 8 ml of anisole and 9 ml of trifluoroacetic acid was added dropwise over 30 minutes with stirring and ice-cooling, followed by stirring for an additional 1.5 hours. Ethyl ether was added and the resulting precipitate was filtered and the precipitate was suspended in water (10 mL). the suspension was adjusted to pH 7 with sodium acellate, the insoluble portion was filtered and the filtrate was purified by reverse phase chromatography on silica gel to give 30 mg of the title compound.

Example 6

7beta- / 2- (5-Amino-l.2.4-thiadiazole-3-yl) - (Z) -2-fluoro-methoxyimino acetamido / 3 - / (E) -3- (4R-hidiOxi2R- hydroxymethyl-1-methyl-1-pyrrolidino) -1-propen-1-yl--3-cephem-4-carboxylate (Compound 13)

700 mg of the compound obtained in Example E4 are quenched in 4 ml of acetone, 89 mg of N-melil-cis-4-hydroxy-D-prolinol in 2 ml of acetone are added, the resulting solution is stirred overnight, and 100 ml of ethyl ether are added. the precipitate is filtered off. 700 mg of a yellow powder are obtained.

The above powder was mixed with 4.5 ml of anisole, 5.3 ml of trifluoroacetic acid was added dropwise over 30 minutes with stirring and ice-cooling, and stirring was continued for 1.5 hours. To the reaction mixture was added 50 ml of isopropyl ether, the precipitate was filtered off, the precipitate was suspended in 30 ml of water and the suspension was adjusted to pH 7 with sodium acetate. The insoluble material is separated by filtration and the filtrate is purified by reverse phase chromatography on silica gel to give the following two isomers (relative to the nitrogen content of the pyrrolyl ring):

6-1 isomer 27 mg

6-2 isomers 100 mg.

Example 7

7β- (2- (5-Amino-1,2,4-thiadiazol-3-yl) - (Z) -2-fluoromethoxy-amino) -acelamido (-3) - (E) -3- (4R) -hydroxyl (2-hydroxyethyl) -2S-hydroxymethyl-1-pyrrolidinium / 1-propen-1-yl / -3-cefinine-4-carboxylate (Compound 14).

g of the compound obtained according to Example IZ4 in 5 ml of diinet.il6

To a solution of 450 mg of (R) -4-hydroxy-1- (2-hydroxyethyl) - (S) -2-hydroxymethylpyrrolidine in formamide is added, the resulting solution is stirred overnight, and then treated with ethyl acetate. acetate was added and the precipitate was collected by filtration to give 1.65 g of a yellow powder.

The above powder was mixed with 10 ml of anisole and added dropwise over 30 minutes with 11.7 ml of trifluoroacetic acid under ice-cooling and stirring for an additional 1.5 hours. Isopropyl ether is added, the precipitate is filtered off, the precipitate is suspended in 4.5 ml of water and the pH is adjusted to 7 with sodium acetate. The insoluble material is filtered off and the filtrate is purified by reverse phase chromatography on silica gel to give the following two different isomers (relative to the pyrrolidine nitrogen atom):

7-1 isomer 96 mg

7-2 Isomer 207 mg.

Example 8

7béta- / 2- (5-amino-l, 2,4-thiadiazol-3-yl) - (Z) -2-fluoro-methoxyimino acetamido / 3 - / (E) -3- (4R-hidroxi2S- hydroxymethyl-1-methylpyrrolidinio) -1-propen-1-yl / -3-cephem-4-carboxylate (Compound 15)

700 mg of the compound obtained in Example E4 are dissolved in 4 ml of acetone, 89 mg of N-methyl-trans-4-hydroxy-L-proline are dissolved in 2 ml of acetone and the resulting solution is stirred overnight. Ethyl ether (100 mL) was added and the resulting precipitate was filtered to give 700 mg of a yellow powder.

The above powder was mixed with 4.5 ml of anisole, 5.3 ml of trifluoroacetic acid was added dropwise with stirring and ice-cooling for 30 minutes, and the resulting mixture was stirred for 1.5 hours. 50 ml of isopropyl ether are then added, the precipitate is filtered off, the precipitate is suspended in 30 ml of water and the suspension is adjusted to pH 7 with sodium acetate. The insoluble material was separated by filtration and the filtrate was purified by reverse phase chromatography on silica gel to give 92 mg of the title compound.

Example 9

7β- [2- (5-Amino-1,2,4-thiadiazol-3-yl) - (Z) -2-fluoromethoxyiminoacetamido] -3- (E) -3- (1-carbamoyl) of methyl 1-3-hydroxy-l-1-pyridine idino) -1-propene-1- [3-cephem-4-carboxylate (Compound 16) g of the compound obtained in Example E4 is dissolved in 4 ml of dimethylformamide. To the solution was added N-carbamoylmethyl-3-hydroxypyrrolidine (186 mg) in dimethylformamide (2 mL) and stirred overnight. Ethyl ether (200 mL) was added and the precipitate was filtered to give 970 mg of a yellow powder.

The above powder was mixed with 9 ml of anisole, and 10.6 ml of trifluoroacetic acid was added dropwise over 30 minutes with stirring and ice-cooling. The resulting mixture was stirred for a further 1.5 hours, then 80 ml of isopropyl ether was added to the reaction mixture, and the precipitate was collected by filtration. The precipitate is then suspended in 50 ml of water. the suspension was adjusted to pH 7 with sodium acetate, the insoluble matter was filtered off and the filtrate was purified by reverse phase chromatography on silica gel. In this way, the various isomers (4 types based on the pyrrolidine nitrogen atom and the 3-position carbon atom can be detected by high pressure liquid chromatography) are as follows:

9-1 isomer 71 mg (a mixture of two different isomers) 9-2 isomer 70 mg (one substance)

9-3 isomer 54 mg (single material).

Example 10

7bcta- / 2- (5-Amino-1,2,4-thiadiazol-3-yl) - (Z) -2-fluoro-methoxyimino acetamido / 3 - / (E) -3- (l- Methyl 4-sulfo-1-piperazinyl) -1-propen-1-yl] -3-cephem-4-carboxylate (Compound 17) g from 4-methylpiprazinosulfonic acid sulfate (718 mg) in 2 mL of N-methyl Add a solution of -N- (trimethylsilyl) -trifluoroacetamide and 6 ml of dimethylformamide and stir overnight. Methanol (2 mL) was added and the insoluble material was filtered off. A mixture of ethyl acetate (50 mL) and ethyl ether (50 mL) was added to the filtrate and the precipitate was filtered to give 1.79 g of a yellow powder.

The above powder was mixed with 10.9 ml of anisole, 12.7 ml of trifluoroacetic acid was added dropwise over 30 minutes with stirring and ice-cooling, and the resulting solution was stirred for an additional 1.5 hours. To the reaction mixture is added 100 ml of isopropyl ether, the precipitate formed is filtered off, the precipitate is suspended in 4.5 ml of water and the suspension is adjusted to pH 7 with sodium acetate. The insoluble material was collected by filtration and the filtrate was purified by reverse phase chromatography on silica gel to give 50 mg of the title compound.

//. example

7béta- / 2- (5-Amino-1,2,4-thiadiazol-3-yl) - (Z) -2-fluoro-methoxyimino acetamido / 3 - / (E) -3- (l- Carbamoylmethyl-4-hydroxy-1-piperidinio) -1-propene-1 H -carboxylate 4-carboxylate (Compound 18) g. The 4-hydroxypiperidine and the resulting solution were stirred overnight. 100 ml of a 2: 1 mixture of ethyl ether and isopropyl ether are added and the resulting precipitate is filtered off with 1 g of a yellow powder.

The above powder was mixed with 9 ml of anisole and 10.6 ml of trifluoroacetic acid was added dropwise with stirring and ice-cooling for 30 minutes, and the resulting solution was stirred for an additional 1.5 hours. To the reaction mixture was added 80 ml of isopropyl ether, the resulting precipitate was filtered off, the precipitate was suspended in 5 ml of water and the pH of the suspension was adjusted to 7 with sodium acetate. The insoluble material was collected by filtration and the filtrate was purified by reverse phase chromatography on silica gel to give 166 mg of the title compound.

HU 207 088 Β

Example 12

7béta- / 2- (5-amino-l, 2,4-thiadiazol-3-yl) - (Z) -2-fluoro-methoxyimino acetamido / 3 - / (E) -3- (5- aza-1-methyl-2,8-dioxabicyclo [3.3.1] nona-5-yl) -1-propen-1-yl) -3-cephem-4-carboxylate (Compound 19)

The compound obtained in Example E4 is dissolved in 10 ml of dimethylformamide and 800 mg of 5-aza-1-methyl-2,8-dioxabicyclo [3.3.1] nononone are added at room temperature and the resulting solution is stirred for 20 minutes. The reaction mixture was then diluted with ethyl acetate (20 mL) and ethyl ether was added to give a brown precipitate (3.85 g).

The above precipitate was dissolved in anisole (23 ml), trifluoroacetic acid (26 ml) was added under ice-cooling and the resulting solution was stirred at this temperature for 30 minutes. Ethyl ether is added, the precipitate is filtered off, the precipitate is suspended in 40 ml of water and the suspension is adjusted to pH 7 with sodium acellate. The insoluble material was collected by filtration and the filtrate was purified by reverse phase chromatography on silica gel to give 408 mg of the title compound.

1-12. Examples 13-113, which are summarized in the following Table, were prepared starting from the compound 20 obtained in Example E4 and the compound A 'to give the compounds of the invention corresponding to the compound 21.

Corresponding to the ammonio group on group A, several isomers are formed. When these isomers have been separated, the corresponding yields refer to the corresponding isomers. The following abbreviations are used in the table:

Boc: tert-butoxytecarbonyl group tBu: tert-butyl group

Bh: benzhydryl

Tr: trityl group.

The amount of starting compound Pclda number THE A '(amine) Example E4 Kiterme- Meeting 13 Group 22 183 mg 800 mg isomer (13-1) 29 mg isomer (13-2) 33 mg is a mixture of the two isomers 14 mg 14 Group 23 107 mg 600 mg 8 mg 15 Group 24 169 mg 1.0 g isomer (15-1) 23 mg isomer (15-2) 35 mg 16 Group 25 187 mg i.o g 114 mg 17 26 is a group 203 mg 1.0 g 33 mg 18 Group 27 Compound 31 1.0 g 23 mg (By-product of Example 17) 19 Group 28 247 mg 600 mg 85 mg 20 29 100 mg 500 mg 90 mg 21 30 is a group 136 mg 1.0 g 64 mg 22 32 is a group 345 mg of compound 33 1.0 g 40 mg 23 34 131 mg 700 mg isomer (23-1) 13 mg isomer (23-2) 13 mg 24 35 544 mg 2.0 g 226 mg 25 36 groups 344mg 1.0g 17 mg

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Example number THE The amount of starting compound Kiterme- Meeting A '(amine) Example E4 26 37 229 mg (hydrochloride) 1.0g 112 mg 27 38 288 mg 730 mg 105 mg 28 39 250 mg I g 6 mg 29 40 groups 200 mg 1g 17 mg 30 Group 41 220 mg 1g 10 mg 31 Group 42 200 mg 1g 30 mg 32 Group 43 200 mg 1g 22 mg 33 Group 44 260 mg of compound 45 750 mg 90 mg 34 Group 46 410 mg of compound 47 750 mg 50 mg 35 48 is a group 230 mg 1g 56 mg 36 49 200 mg 1g 22 mg 37 Group 50 150 mg 500 mg 22 mg 38 Group 51 180 mg 1g 20 mg 39 52 is a group 160 mg lg 35 mg 40 53 298 mg 1g 218 mg 41 Group 54 159 mg 800 mg 20 mg 42 55 260 mg 800 mg 6 mg 43 56 274 mg 1g 80 mg 44 57 is a group 100 mg 550 mg 89 mg 45 58 160 mg 550 mg 16 mg 46 CH -'n'N / OH Lconh, 220 mg / CH, λ iq / X / OH yJ'CONH, J 'g 26 mg 47 CH .1. - N-G / OH Lcooh 1g 19 mg (by-product of Example 46) 48 CH - N- ^ CONHj LcONH, 608 mg 3g 145 mg 49 OH r J - nx ^ conh, ^ H 913 mg (hydrochloride) 2g 3 mg

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Example number THE The amount of starting compound Kiterme- Meeting A '(amine) Example E4 50 .OH • Y - | and, / CH3 V, OH OH 200 mg 1g 23 mg 51 OH - N ^ / NHCOCH, 200 mg > g 13 mg 52 λ / ° ^Η / Υ ^η - N / \ / N V, N ^ \ OH OH 194 mg 500 mg 46 mg 53 ch, - N — NHCONHj CH 166 mg 1g 8 mg 54 CH .1 - N - OH 1 CH 2.5 mi 1g 15 mg 55 CH - N- ^ CONHCH, ah, 381 mg 2g 250 mg 56 CH • 1 / CH, -m ^ CONI 1 CH, CH ill mg 500 mg 87 mg

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Example number THE The amount of starting compound Kiierme- Meeting A '(amine) Example E4 57 CH, CH, —N --- CH, CH, V ^C0NH ' 250 mg 800 mg 63 mg 58 CH, θ ^Η 3 '- N \ CONHCH, CH, 157 mg 750 mg 52 mg 59 CH, CH, -A Ah I ^X CONHCH, CH, 157 mg 750 mg 41 mg 60 CH, +1 / -CONH, - N-6-H Ah, ^conh ' 445 mg 2g 75 mg 61 CH,. | ) —CONH, - N-CH, ^C0NH = 445 mg 2g 268 mg 62 CH .1 / —oh —- HIUI PJ Au, 3.39 g 23.8 g 1.42 g 63 CH, .1 λ- ° ^η - N-6 H 1 'CONHCH, OH Urij 200 mg 500 mg 14 mg

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The amount of starting compound Example S2áma THE A '(amine) Example E4 Kiicrme- Meeting 64 CH .1 - ΝΆ / ΟΗ 1 CH 81 pl 500 mg 101 mg 65 _{CH3 H} CH, ^0H 150 mg 750 mg 127 mg 66 CH -N / 'Y'CH. CH, Ο » 150 mg 750 mg 120 mg 67 CH,. JZv / OH 1 CH 300 mg 1g 126 mg 68 CH 4¾ j \ -OH CH 300 mg 1g 126 mg 69 CH, CH, - N - CH, CH, ^L0H 400 mg 1g 35 mg 70 , -OH-Ν-4 / ΌΗ CH, ¹ -OH 361 mg 1.5 g 15 mg

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Example number THE The amount of starting compound A '(amine) Example E4 Kiterme- Meeting 71 CH .1 - N ^ CONHOCH, 1 CH 71 mg 500 mg 6 mg 72 CII, - N ^ CONHOH 1 CH 301 mg <CH, \ \ {CH ^ N ^ CONIIO-TrJ 800 mg 25 mg 73 CH -Y ^ ^ CON CONI CII, 150 mg 800 mg 52 mg 74 CH, ·! z ^ ° ^H —N ^ CON l ^ Xjh CH, 110 mg 500 mg 74 mg 75 CH CONH -N ^ / S / OH 1 CH 260 mg 500 mg 48 mg 76 CH, CH, —N-aJk ^ coo1 1 CH, CH, 373 mg fcH- ^N '4 ^XSC0 ° -' ^B I) 8. 'CHj Br' - ⁷ 730 mg 16 mg 77 CH CH 158 mg 800 mg 88 mg

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Example number _ THE The amount of starting compound Kiterme- Meeting A '(amine) Example E4 78 cn, ch, ^oh 138 mg 800 mg 36 mg 79 59 115 mg 500 mg 92 mg 80 60 70 mg 500 mg 4 mg 81 61 131 mg 500 mg 30 mg 82 62 270 mg 750 mg 70 mg 83 63 335 mg 750 mg 67 mg 84 64 formula groups 268 mg 750 mg 65 mg 85 65 220 mg 750 mg 32 mg 86 66 is a group 300 mg 1.5g 97 mg 87 CH .1 - NA / NHCH, 1 CH 326 mg \ CH, CH, y 1g 130 mg 88 CH, - Ν / γ \ θΗ CH, ^0H 192 mg ¹ g 36 mg 89 j 67 is a group 250 mg 1.5g isomer (89-1) 28 mg isomer (89-2) 62 mg ! 90 68 156 mg 1.05 g 107 mg 91 69 187 mg 1g 56 mg í ! ! 92 Ϊ 1 1 CH,. , | - N ^ CONH ^ OH CH 350 mg 1.2 g 67 mg

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Example number THE The amount of starting compound Kiterme- Meeting A '(amine) Example E4 93 CH - il / XZCONH, CH 150 mg 1g 97 mg 94 70 203 mg 100 mg 25 mg 95 CH, J / - OH - N - (| ^{5 -} OH CH, 180 mg 1-2 g 50 mg 96 J-CH - N ^ CONH, '-CH 420 mg 2g 98 mg 97 CH - N'V'CONHCH, 1 CH 90 mg 600 mg 7 mg 98 CH CH 90 mg 600 mg 7 mg 99 CH -'j ^^ X / OCH 1 CH 132 mg ¹ g 19 mg

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Example number THE The amount of starting compound Kiterme- Meeting A '(amine) Example E4 100 CHa .1 Aoh? pi ^H CHj ^ —eONH: 470 mg 2g 40 mg 101 A group of 71 kcp 391 mg ¹ g 62 mg 102 72 130 mg 500 mg 35 mg 103 73 150 mg 500 mg 30 mg 104 CHj - N ^ CONHSOjNH, CH ₃ 300 mg 1g 12 mg 105 CWhen .1 - N- ^ CONHSOjCFI, CWhen 150 mg 500 mg 12 mg 106 74 120 mg 500 mg 30 mg 107 - N-NH, OH 200 mg ¹ g 15 mg 108 75 400 mg 800 mg 21 mg 109 76 groups 720 mg 1g 43 mg 110 77 is a group 545 mg 1g 33 mg 111 78 670 mg of compound 81 1g 6g 112 Group 79 133 mg (hydrochloride) 500 mg 31 mg 113 Group 80 280 mg (hydrochloride) 500 mg 28 mg

Example 114

7béta- / 2- (5-amino-l, 2,4-thiadiazol-3-yl) - (Z) -2-fluoro-methoxyimino acetamido / 3 - / (E) -3- (dimethyl- B · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · (bamoylmethylammonio) -1-propen-1-yl / -3-cephem-4-carboxylate (Compound 82)

500 mg of the compound obtained in Example E6 are dissolved in a mixture of 10 ml of ethyl acetate and 10 ml of ethyl ether, 160 mg of dimethylglycine amide are added and the mixture is stirred for 30 minutes at room temperature. Isopropyl ether was then added to the solution and the precipitate was filtered off and dried to give 400 mg of a tan powder.

This powder was stirred under ice-cooling with a mixture of 5 ml of trifluoroacetic acid and 4.5 ml of anisole and stirred for 1 hour. Ethyl ether was added and the precipitate was filtered off, washed with ethyl ether, suspended in water (5 mL) and adjusted to pH 5.5-6.5 with sodium acetate. The insoluble material was separated by filtration and the filtrate was purified by reverse phase chromatography on silica gel to give 55 mg of the desired product.

Similarly, ve165-117, summarized in the following table, was prepared

The compounds of formula E6 or formula 84 are obtained starting from the compound and compounds A ', whereby the compounds are summarized in the following table.

Example number THE The amount of starting compound Kiterme- Meeting A '(amine) Example E4 115 85 389g 1g 4g 116 86 I20mg 600mg 78mg 117 - bKV-OH ^ OH 220mg 700mg 30mg

Physical data

Example number IR spectrum (cm ^-1 , Nujol) NMR Spectrum (δ) 1 1735.1530 _(DMSO-d6) 1.19 (3H, t, J = 7Hz), 4.21 (2H, q, J = 7Hz), 5.79 (2H, d, J = 55 Hz), 7.30 (15H, s), 03.10 ( H, s) 2 1720.1585 _(DMSO-d6) 5.78 (2H, d, J = 55 Hz), 7.31 (15H, s), 10.06 (1Ή, s) 3 1765, 1725, 1680, 1610 _(DMSO-d6) 3:45 (IH, d, J = 18Hz), 3.63 (IH, d, J = 18Hz), 3.75 (3H, s), 3.95 (IH, dd, J = 8 Hz, 12 Hz ), 4.12 (1H, dd, J = 8Hz, 12Hz), 5.07 (1H, d, J = 12Hz), 5.14 (1H, d, J = 12Hz), 5.24 (1H, d, J = 5) Hz), 5.70 (1H, m), 5.78 (2H, d, J = 55Hz), 5.85 (1H, m), 6.26 (1H, d, J = 12Hz), 6.92 (2H, d, J = 9 Hz), 7.25-7.4 (17H, m), 9.74 (1H, d, J = 8Hz), 10.08 (1H, s) 4 1770, 1715, 1685, 1610 (CDCl 3) 3.51 (1H, d, J = 18Hz), 3.60 (1H, d, J = 18Hz), 3.81 (3H, s), 3.98 (2H, d, J = 8Hz), 5.04 (1H, d, J = 5Hz), 5.19 (1H, d, J = 12Hz), 5.24 (1H, d, J-12Hz), 5.82 (2H, d, J-55Hz), 5.90 (1H, m), 6.14 (1H, dt, J-8Hz, 16Hz), 6.77 (1H, d, J = 9Hz), 6.90 (2H, d, J-9Hz), 7.00 (1H, d. J-16 Hz), 7.2-7.4 (17H, m), 7.83 (1H, s) 5 1775, 1725, 1690, 1610 (CDCl ₃ ) 3.34 (1H, d, J = 18.5 Hz), 3.52 (1H, d, J = 18.5 Hz), 3.75 (1H, dd, J = 12.1 Hz, 8.5 Hz), 3.80 (3H, s), 3.93 (1H, dd, J-8.5 Hz, 12.1 Hz), 5.10 (1H, d, J-5.0 Hz), 5.14 (2H, s), 5.74 (1H, dt, J-8.5 Hz, 11.0 Hz), 5.92 (1H, dd, J = 5.0 Hz, 8.8 Hz), 6.25 (1H, dd, J = 11.0 Hz), 6.79 (1H, d, J = 8.8 Hz), 6, 81 (1H, t, J = 71.2Hz), 6.87 (2H, d, J = 8.7Hz), 7.15-7.25 (6H, tn), 7.29 (2H, d) , J = 8.7 Hz), 7.25-7.40 (9H, m), 7.67 (1H, brs) 6 1780, 1720, 1690, 1610 (CDCl3) 3.51 (1H, d, J = 17.6 Hz), 3.61 (1H, d, J = 17.6 Hz), 3.81 (3H, s), 3.98 (2H, d, J = 8.0 Hz), 5.05 (1H, d, J = 5.0 Hz), 5.21 (2H, brs), 5.89 (1H, dd, J-4.8 Hz, 8.8 Hz), 6.14 (1H, dt, J-8.0 Hz, 16.0 Hz), 6.78 (1H, d, J-8.8 Hz), 6.81 (1H, t, J = 71.2 Hz), 6.90 (2H, d, J = 8.8 Hz), 7.00 (1H, d, J = 16.0 Hz), 7.15-7.45 (17H, m), 7.63 (1H, brs)

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Pclda number IR spectrum (cni''Nuiol) Nuclear Magnetic Resonance Spectrum (8) 1760. 1675.1590. 1520 _(DMSO-d6) 1.26 (3H. T. J = 7.2 Hz.). 3.08 and 3.09 (total 3H. S), 3.4-3.6 (2H. Ni). 3.47 (1H. T. J = 16.8 Hz), 3.65 (1H. D, J = 16.8 Hz). 4.01 (211 s), 4.05-4.2 (2H. Ni), 5.06 (111, d. J = 4.8 Hz). 5.6-5.75 (2H. Ni). 5.79 (2H. Brd, J = 55.3 Hz). 7.17 (1H, d. J = 15.8 Hz). 7.66 (1H.s). 8.23 (2H, s), 8.33 (1H, s). 9.71 (1H d. J = 8.4 Hz.) 2-1 1750.165 (). 1590.1520 (D-, O) 2.18-2.30 <4H. ni). 2.78-2.83 (1H. M), 3.48-3.54 (4H. Ni). 3.7 ^ 3-3.84 (411. ni). 4.15-4.18 (2H. Ni). 4.32 (2H. Ni), 5.38 (1H. D. J = 5.1 Hz). 5.94-6.00 (1II. Ni). 5.96 (211. d, J = 54.2 Hz.). 5.97 (I H d. J = 5. 1 Hz). 7.07 (1H.tl. J = 16.8 Hz.) 2-2 1750. 1650. 1590, 1520 (D ₂ 0) 2:19 to 2:26 (4H, m), 2.76-2.81 (IH. Ni). 3.42-3.54 (2 H, m). 3.65-3.66 (2H, ni), 3.73-3.83 (4H, m). 4.14-4.16 (2H, m), 4.24-4.27 (2H. Ni), 5.39 (1H, d. J = 5.1 Hz). 5.96 (2H, d, J = 54.6 Hz), 5.97 (1 H, d, J = 5.1 Hz). 5.99-6.07 (1 H. m). 7.02 (1H, d, J = 15.8 Hz) 3-1 1760. 1670. 1590, 1515 _(DMS0-d6) 1:48 (3H, d. J = 7.0 Hz), 3:05 (3H, s), 3:08 (3H. S), 3:48 (111, d. J = 16.7 Hz). 3.65 (1H.d. J = 16.7 Hz). 3.97-4.15 (3 H, m). 5.07 (I H. d .1 = 5.0 I Izz). 5.66 (1H. Dd .1 = 5.0 Hz, 8.4 Hz), 5.65-5.75 (1H. M), 5.78 (211 brd. J = 55.5 Hz), 7.15 (111 d. J = 15.8 Hz). 7.70 (1H, s). 8.12 (2H. S). 8.26 (1 H. s). 9.70 (1H d .1 = 8.4 Hz) 3-2 1760. 1670. 1590. 1520 (DMSO-d _h) 1:46 (311 d. J = 7.0 Hz). 3.04 <3H. s). 3.06 (311s). 3.49 (1H. Ti. J = 17.2 Hz). 3.64 (I H. d. J = 17.2 Hz). 4.05 (1H, ni). 4.15-4.30 (211. ni). 5.09 (1 H. ti. 1 = 5.0 1 Is). 5.67 (1H, dd. J = 5. () Hz, 8.0 Hz). 5.5-5.8 (111. ni). 5.79 (2H. Brd .1 = 55.5 Hz). 7.18 (1H, d, J = 15.4 Hz). 7.67 (1I I. s). 8.21 (2 H, s). 8.64 (1H. S). 9.70 (1H, d, J = 8. () Hz) 4 1765. 1660. 1600. 1525 (DMSO-tl _ft ) 1.11 (3l-d. D. J = 6.2 1 Iz). 3.01 (31-1 s). 3.04 (31-1, s), 3.22 (211, bits. J = 7.0 Hz). 3.46 (111 d. J = 17.0 Hz), 3.63 and 3.65 (total 1H. I.e. J = 17.0 Hz). 4.06 (brd. 211 J = 6.2 Hz). 4.26 (1H. Brs). 5.06 (1H. D .1 = 5.0 Hz). 5.6-5.75 <2H. ni). 5.79 (2H. Brd .1 = 55.3 Hz), 7.16 (1H. D. J = 15.8 Hz). 8.27 (2H.s). 9.71 (1H, J = 8. 1 Hz.) 5 1765. 1670. 1600. 1530 (DMSO-tI ₍ ,) 3.08 (311 s). 3.14 (311 s). 3.49 (1I I. d, .1 = 17.2 Hz). 3.62 (111 i.e., .1 = 17.2 Hz). 3.87 ( 111, dtl, .1 = 5.5 Hz, 12.5 Hz) 4.06 (1H, dd. J = 5.5 1 Iz, 12.5 Hz) 4.1 -4.2 (111 ni) 4.19 (2H, d .1 = 7.3 Hz) ) 5.08 (1H, d. J = 5.0 1 Iz) 5.67 (Ill. Dtl..1 = 4.8 1 T 8.8 Hz) 5.70-5.85 (111, m) 5.79 (21-1. .1 = 55.0 Hz) 7.11 (11-1. Ti .1 = 15.4 Hz) 7.76 (1H.s), 8.22 (2H.s) 8.52 (lil.s) 9.73 (1H.tl. .1 = 8.4 11 /) 6-1 1750. 1650. 1590, 1510 (DMSO-t ₆ ) 1.73-1.78 (ΗI. Ni). 2.54-2.60 (1H, ni), 3.04 (3H, s), 3.44-3.86 (5H. Ni). 3.46 (111 d. J = 17.2 Hz), 3.62 (1II, d, J = 17.2 Hz), 4.00-4.23 (2H, ni). 4.43 (111. Ni). 5.06 (1H, d, J = 5.1 Hz), 5.65 (1H, tld. J = 5.1 Hz, 8.4 Hz). 5.71-5.86 (311, m). 7.1 3 (1H, d, J = 15.4 Hz). 8.22 (2H, s), 9.70 (1H, i.e. J = 8.4 Hz) 6-2 1750. 1650. 1590, 1510 (DMSO-d ₍ ,) 1.77-1.83 (1H, ni), 2.53-2.59 (1H, ni), 3.04 (3H, s). 3.32-3.94 (5H, ni) 3.46 (1H, d, J = 16.9 Hz), 3.65-3.71 (1H, m), 3.91-4.19 (2H, ni), 4.45 (1H, ni), 5.07 (1H, d, J = 5.1 Hz), 5.64 (1H, tld. J = 5.1 Hz. 8.4 l-lz) 5.71-5.86 (3H. Ni) 7.14 (1H. Ti, J = 1.5 5.7 Hz) 8.24 (2H.s) 9.70 (1H.tl.1 = 8.4 11 / .) 7-1 1760, 1665, 1590. 1525 (DMSO-tl ₆₎ 2:05 (IH. Ni). 2.31 (111. ni). 3.4-3.9 (1 1H. Ni), 4.01 (1H. Ni). 4.13 (1H, ni). 4.31 (11l-l, brs). 4.42 (1H, brs). 5.07 (1H, d. J = 4.8 Hz)). 5.65 (1H. Dd. J = 4.8 Hz .. 8.4 Hz). 5.76 (1H, m), 5.78 (2H, t. J = 56.6 Hz). 7.14 (1H, d .1 = 15.4 Hz), 8.22 (2H, s), 9.70 (1H, d, J = 8.4 Hz) 7-2 1760. 1665. 1590. 1530 _(DMS0-d6) 2:05 (1H, m). 2.29 (111. Ni). 3.4-3.9 (1H, m), 3.90-4.35 (3H. Ni). 4.44 (1 H. brs). 5.07 (1H, t, J = 4.8 Hz), 5.65 (1H, dtl, J = 4.8 Hz, 8.1 1 Iz), 5.78 (2H, t, J = 55.6 I Iz). 5.79 (1 H. ni). 7.11 (1 H d. J = I5.4 Hz). 8.21 (211s). 9.71 (11.11i, J = 8.1 Hz) 8 1750. 1660. 1590. 1510 (DMSO-d _ft ) 1.95-2.07 (III, in), 2.17-2.35 (Ί H. ni), 2.92 and 3.14 (total 3H. S). 3.22-4.03 (5H. In). 3.45-3.66 (2H. Ni), 4.03-4.22 (2H. Ni). 4.42 (1I I. ni). 5.07 (111. ti.1 = 4.8 Hz), 5.65 (1H, dd, J = 4.8 Hz, 8.1 Hz), 5.71 -5.86 (3H. Ni). 7.11 -7.18 (1I I. ni). 8.22 (2H, s). 9.70 (1H. J. 8.1 Hz)

HU 207 088 Β

Example number IR spectrum (cm ^-1 Nujol) NMR Spectrum 9-1 1750, 1660, 1590, 1510 _(DMSO-d6) 1.95-1.98 (1H, m), 2:30 to 2:36 (1H, m), 3:45 (1H, d, J = 9.16 Hz). 3.59-3.82 (5Η, m) .4.19 (1H, s), 4.24 (2H, m), 4.50 (1H, ni). 5.06 (1H, d, J = 4.8 Hz). 5.65 (1H. Dd. J = 8.1 Hz, 4.8 Hz), 5.69-5.75 (1H, ni), 5.79 (2H, d, J = 55.0 Hz)), 7.10 (114 d, J = 15.8 Hz), 7.66 (1H, s). 8.10 and 8.12 (total 1H, s), 8.22 (2H, s). 9.70 (1H, d, J = 8.1 Hz) 9-2 1750.1660.1590,1510 _(DMS0-d6) 1.97-1.99 (IH, m), 2:40 to 2:42 (IH, m), 3:45 (IH, d. J = 16.9 Hz). 3.60-3.85 (5 H, m). 4.06 (214 s), 4.18-4.32 (2 H, m). 4.51 (1H, m), 5.06 (1H, d .1 = 4.8 Hz). 5.65 (1H. Dd, J = 8.1 Hz, 4.8 Hz), 5.70-5.85 (1H, ni), 5.79 (2H, d, J = 55.3 lz), 7.10 (1H, d, J = 15.4 Hz). . 7.66 tiH. s). 8.15 (1H, s), 8.22 (214, s). 9.70 (1H, d. J = 8.1 Hz) 9-3 1750, 1660, 1590, 1510 (DMS0-d _e) 1.95-1.98 (1H, m). 2.37-2.42 (1H, ni), 3.46 (1H, d, J = 16.9 Hz). 3.60-3.83 (5H, ni). 4.06 (2H, s). 4.26 (2H, m), 4.52 (1H, ni), 5.06 (1H, d, J = 4.8 Hz), 5.65 (1H, dd, J = 8.1 Hz, 4.8 Hz), 5.72-5.84 (1H, m), 5.79 (2H, d, J = 55.0 Hz). 7.10 (1H, d, J = 5.8 Hz), 7.65 (1H, X). 8.18 (1H, s). 8.22 (2H, s), 9.70 (1H, d, J = 8.1 Hz) 10 1765, 1670, 1595, 1525 (DMSO-d _c ) 2.95 (2H, s), 3.0-3.5 (8H, ni). 3.52 (1H, d, J = 16.9 Hz), 3.76 (1H, d, J = 16.9 Hz), 4.08 (2H, ni), 5.12 (1H, d, J = 4.8 Hz), 5.71-5.85 (3H, m) ), 7.14 (1H, d, J = 15.8 Hz), 7.16 (1H, brs), 8.21 (2H, s). 9.74 (1H, d, J = 8.1 Hz) 11 1760. 1650. 1590, 1530 (DMSO-d ₍ ,) 1.74 (214, brs), 2.01 (2H, brs), 3.2-3.8 (6H, ni), 3.81 (1H, s), 4.02 (2H, s), 4.28 (2H, s) 5.05 and 5.06 (total 1H, d. J = 5.1 Hz), 5.6-5.8 (1H. Ni), 5.64 (1H.dd.J = 5.1 Hz, 8.1 Hz) 5.78 (214 d. J = 55.3 7.1 Hz (1H, d, J = 15.8 Hz), 7.71 (11II, s), 8.22 (314, s), 9.69 (114d, J = 8. 1 Hz); 12 1750, 1660, 1610, 1590 (DMSO-d _h) 1:35 (311 s). 3.1-4.0 (1211. m), 4.1-4.3 (114, m), 4.50 (214, d. J = 3.6 Hz). 5.07 (1H, d. J = 4.8 Hz). 5.6-5.8 (2H, m), 5.76 (2H, dd. J = 52.0 Hz). 7.15 (1H. D. J = 15.7 lzz). 8.22 (2H, s), 9.70 (114, d J = 8.0 Hz) 13-1 1760. 1670, 1590, 1520 (DMSO-d 6) 1.50 (3H, d. J = 6.6 Hz). 2.00 (4H, brs), 3.47 (1H, d, J = 17.0 lzz). 3.45-3.70 (311. ni). 3.63 (114 d. J = 17.0 Hz). 3.85-3.95 (114m), 4.07 (2H. Ni), 4.15-4.25 (1H. Ni). 5.07 (1H, d, J = 4.8 Hz), 5.65 (1H, dd. J = 4.8 Hz. 8-0 Hz), 5.7-5.8 (114 ni). 5.78 (2H, d, J = 55.0 Hz). 7.16 (114, d. J = 15.8 Hz), 7.69 (114 s), 8.23 (2H, s). 8.36 (1H, s). 9.71 (1H.d. J = 8.0 Hz.) 13-2 1765, 1680, 1600, 1525 _(DMSO-d6) 1:49 (3H, d, J = 6.6 Hz). 2.00 (4H, brs), 3.47 (1H, d, J = 17.0 Hz), 3.5-3.70 (3H, m), 3.59 (1H, d, J = 17.0 Hz), 3.8-3.9 (1H, ni) . 4.07 (214. ni). 4.25-4.35 (1H. Ni). 5.07 (114, d. J = 5.0 Hz), 5.66 (1H, dd, J = 5.0 Hz, 8.4 Hz), 5.70-5.85 (1H, ni), 5.78 (2H, d, J = 55.0 Hz). 7.16 (114d J = 15.4Hz) 7.69 (1H, s), 8.22 (2H, s), 8.50 (1H, s), 9.70 (1H, d, J = 8.4Hz) 14 1765, 1665, 1595, 1520 (D-, O) 2.35-2.45 (2 H, m). 3.75-4.0 (614, m). 4.3-4.4 (6H, ni), 4.73 (214 s), 5.40 (114, d, J = 4.8 Hz), 5.96 (2H, d, J = 54.5 Hz), 5.98 (1H, d, J = 4.8 Hz) ), 6.09 (1H, dl, J = 8.0 Hz, 15.8 Hz), 7.15 (1H, d, J = 15.8 Hz) 15-1 1750. 1650. 1590. 1510 (DMSO-d _ft) 1.91-1.96 (114, m), 2:32 to 2:41 (IH. M), 3.31-3.99 (I0H, 111). 3.99-4.24 (211. m). 4.50 (1H, ni). 5.06 (114, d. J = 4.8 Hz), 5.65 (1H, dd, J = 4.8 Hz, 8.1 Hz), 5.66-5.72 (114 ni). 5.79 (2H, d, J = 55.3 Hz), 7.16 (1H, d, J = 15.8 Hz), 8.21 (2H, s), 9.70 (1H, d, J = 8.1 Hz). 15-2 1750. 1650. 1590. 1510 (DMSO-yl ₆ , 1.93-1.97 (III. Ni). 2.35-2.42 (III. Ni), 3.34-3.82 (1 OH. 111). 4.09-4.23 <211, m). 4.51 (II I. ni). 5.07 (114 d. J = 4.8 Hz), 5.65 (1I I. dd. J = 4.8 Hz. 8.1 Hz). 5.72-5.82 (114, ni). 5.79 (214, d, J = 53.9 Hz). 7.15 (1 H d. J = 15.8 Hz). 8.21 (214s). 9.70 (1H, d, J = 8.1 Hz) 16 1740, 1640. 1580 (DM.SO-d ₆ } 1.8-2.3 (414 ni). 3.4-4.2 (1114 m). 3.97-4.13 (2H, m), 5.07 (1H. D. J = 5.1 Hz), 5.64 (114 dd. J = 5.1 Hz, 8.4 Hz), 5.71 -5.78 (114 ni), 5.79 (214, d, J = 55.3 Hz), 7.15 and 7.16 (total 114, d, J = 15.8 Hz) 8.22 ( 214. s) 9.70 (114, d J = 8.4 Hz) 17 1750. 1660. 1590 (DMSO-d _ft ) 1.8-2.3 (414, m). 3.3-4.4 (914, ni), 4.01-4.29 (214, m). 5.07 (11I, d. J = 4.8 Hz), 5.66 (114d, J = 4.8 lz. 8.1 Hz). 5.76 (1H, m). 5.78 (114d J = 57.5Hz), 7.14 (114d J = 15.4Hz), 7.61 (1H, s), 8.21 (IIIs). 8.24 (214, s), 9.72 (114, d, J = 8.1 Hz.)

HU 207 088 Β

Example number IP Spekirum (c m ' ¹ N ti well) NMR spectacle (6) IX 1760. 1650. 1600. 1520 (DMSO-d ₍ ,) 1.92-2.20 (4H, ni). 3.40-3.75 (4H, m), 3.43-3.75 (2H, ni), 3.X6 (1H, m). 4.0X (1H, m)) 4.66 (111, m) 5.05 UH, i.e. 4.8 Hz), 5.63 (111 dd.> 8.4 Hz. 4.X Hz). 5.6X-5.76 (1 H. ni). 5.79 (2H, d, > 55.3 Hz). 7.12 (1H. D. J = 15.X1 Taste). X.22 (2H, s), 9.71 (1H, d, > 8.4 Hz) 19 _(DMS0-d6) 2:06 (411, brs). 3.45 (Dec. 111, J = 17.2 Hz). 3.5-3.7 (511. in). 4.05 (2H.s). 4.13 (2H. Brs), 5.06 U ld> 4.8 Hz). 5.65 (111, dd.> 4.8 Hz. XO Hz). 5.65-5.8 (111, ni). 5.7X (2H. Brd.> 55.0 Hz). 7.12 (1H. D.> 16.2 Hz). 7.66 (1 H. s). X.23 (311. s). 9.70 (1H, d, J = X0 Hz.) 20 _(DMSO-d6) 2:05 (4H, brs), 3:44 (IH. D. J = 16.X Hz) 3.50 (6H, brs), 3.63 (IH. D,> 16.X Hz). 4.8-4.9 (2H, m), 4.01 (2H, d. &Gt; 7.3 Hz). 5.06 {1H. d. .1 = 5.0 Hz), 5.64 (1H, dd,> 5.0 Hz, 8.0 Hz), 5.7-5.8 (1H, ni), 5.78 (2H, brd.> 56.0 Hz), 7.17 (III. D, J = 15 .8 Hz). 8.23 (2H, s) .9.70 (1H.d,> 8.0 Hz) 21 (DMSO-d _h) 1.75-2.25 (4H. M), 2.xx (111, s). 3.06 (2H, s); 3.2-4.3 (9H. Ni). 3.45 (1 H. ti. J = 16.9.). Hz). 3.68 (1H d. J = 16.9 Hz, 5.05 (1H. D.> 4.8 Hz). 5.6-5.8 (Hl. Ni). 5.63 UH. Dd, J = 4.8 Hz, 8.4 Hz), 5.78 (2H, i.e., > 58.6 Hz), 7.15 and 7.1X (loial H1, d. > 15.4 Hz), 8.23 (2H, s). 9.69 (1H. T. .1 = 8.4 Hz) (D ₂ O) 2.34 (411 s). 3.5-3.9 UOH. ni). 4.17 (2H. D .1 = 7.7 Hz), 5.39 (1H. T .1 = 4.8 Hz). 5.97 (1II, i.e. .1 = 4.8 Hz). 5.97 (211st.> 54.6Hz). 6.00-6.15 UH. m). 7.07 (1H. Th. .1 = 15.8 Hz) 23-1 ! 1750, 1650. 15X0 (DMSO-tl _ft ) 2.06-2.08 (31-1, ni). 3.21-3.63 (12H. Ni), 4.02-4.08 (2H. Ni), 5.08 (1H. Th .1. = 5.1 Hz). 5.66 (i H. dd, .1 = 5.1 Hz. 8.1 Hz), 5.71-5.76 (1 H. ni). 5.79 (2H. Ti. J = 55.3 lz). 7.13 (1H, d. J = 15.8 Hz), 8.21 (2H, s). 9.71 (II-l.tl. J = X1 Hz) 23-2 1750. 1650. 15X0 (DMSO-d _h) 2.0X (311 ni). 2.98-3.07 (2H. In). 3.36-3.80 (9H, ni), 3.98-4.02 (1H. Ni). 4.07-4.12 (2H. Ni). 5.06 UH, d, > 4.8 Hz), 5.66 (1H, tld .1 = 4.8 Hz, X. 1 Hz). 5.71-5.85 (3H. Ni). 7.06 (1H, cl, J = 15.8 Hz). X.20 (21 ls). 9.75 (ll.tl.> XI Hz) 24 1765, 1650, 1595, 1525 _(DMSO-d6) 3:06 (31-1. S). 3.3-3.5 (411. ni), 3.46 (1H, ti,> 16.9 Hz), 3.5-4.0 (4H. Ni), 3.64 (1H, d.> 16.9 Hz), 4.15 (2H, ni) , 5.06 (1H, d. J = 4.8 Hz). 5.6-5.8 (1I I. ni), 5.64 (1H, tld.> 4.8 Hz. 8.4 Hz), 5.79 (2H, (1 .1 = 57.2 Hz), 7.22 (1H.tl..i = 15). 8 Hz.) X.08 (1H, s), 8.23 (2H, s), 9.70 (1H.d.> 8.4 Hz). 25 1750. 1650. 1620, 15X0 (DMSO-t1) 2.55-2.90 (10H. Ni). 2.97 (3H, s), 3.1-3.5 (sH, in), 3.4X UH, (1..1 = 17.6 Hz). 3.75 (1H.d. > 17.6 11 /.). 4.0-4.2 (2H, m), 5.12 (1H, d .1 = 5.1 Hz). 5.65-5.80 Η11. ni). 5.80-5.90 (111, ni), 5.79 (2H, d, > 55.3 Hz), 7.11 (1H.d., 15.8 Hz). 8.21 <2H.s), 9.73 (1H. D,> 8.1 Hz) 26 1765, 1670, 1590, 1530 (DMSO-t1) 2.28 (311 s). 3.10 (311s). 3.46 (1H, d, J = 16.9 Hz), 3.6-4.1 (811. ni). 3.64 (11-1h, > 16.9Hz), 4.16 (2H, in), 5.07 (1H, d, > 4.8Hz), 5.6-5.X (1H, ni), 5.79 (211d, > 57.2) Hz), 5.66 (1H, dd, .1 = 4.8 Hz. 7.7 H /). 7.22 UH. you. > 15.4 Hz), 8.23 (2H, s). 9.70 (1H.d, .1 = 7.7 Hz) 27 1760, 1660, 1590. 1520 (DMSO-d6) 2.49-3.85 (16H, m). 3.42-3.5 (1H, in), 3.66 (1H, d, > 17.2 Hz). 4.17 (2H. D.> 6.6 Hz). 5.06 (1H, d, J = 4.8 Hz), 5.6-5.9 (1H, m), 5.64 (111, tld, J = 4.8, 8.1 Hz), 5.79 (2H, d, > 55.3 Hz), 7.17 U11, d. > 15.8 Hz), 8.24 (211 s). 9.70 (! H, d, > 8.1 Hz) 28 1750. 1650. 15X0 (D ₂ O) 3.6-3.85 (XH. Ni). 3.85-3.97 (4H, ni), 4.19 (2H, t, > 4.8 Hz), 4.39 (211 ni). 5.39 (1H. Ti. 1 = 4.8 Hz). 5.96 (2H, d, > 54.2 Hz), 5.97 (111, d, J = 4.8 lz). 6.0-6.08 (111. in). 7.06 (111 d,> 15.7 Hz) 29 j 1750, 1660, 15X0 (DMSO-d6) 3.2-3.7 (12H, ni), 3.8 (2H, m), 4.22 (211, (1..1 = 7.3 Hz)). 5.08 (Ill. D.> 5.1 Hz). 5.6-5.8 (211. ni). 5.79 (d. 211> 55.7 Hz). 7.13 (2H, s), 7.18 (1H, d, > 15.8 Hz). X.22 (2Π, s), 9.70 (1H, ti,> 8.0) 30 1 (D ₂ O) 3.5-4.0 (14H. In). 4.35-4.55 (3H. In), 5.38 (1H, d, J = 4.7 Hz), 5.95 (211 d, J = 54.2 Hz). 5.97 (1II. D .1 = 4.7 Hz). 6.0-6.5 (1H, m). 7.06 (IH.d,> 15.4 Hz)

HU 207 088 B

Example number IR spectrum (cm -1 ^L Nujol) NMR Spectrum 31 1750. 1650. 1580 (Λλ, Ο) 3.75-4.00 (1 OH. Ni), 4.2.3 (1H. Th. J = 16.4 Hz), 4..30 (1H, cl, 1 = 1.6 Hz). 4.5.3 (2H, d, J = 8.1 Hz). 5.39 (1H, d, J = 4.8 Hz). 5.95 (2H, d .1 = 54.2 Hz), 5.97 (1H. D. 1 = 4.8 Hz). 6.0-6.05 (1H, m). 7.05 (1H, d. 1 = 15.8 Hz) 32 1750. 1640, 1580 (D, O) .3.55-4.0 (1411. m). 4.25-4.40 (211. ni). 5.39 (1H, d, J = 4.7 Hz). 5.97 (1H, d, J = 4.7 Hz), 5.98 (2H, d, J = 5.3.4 Hz), 6.04 (1H, m), 7.08 (1H, d, J = 15.7 Hz). 33 1750. 1660, 1620, 1580 (DMSO-d ₆ ) 2.8 -3.3.4 (1 OH. Ni). 2.97 (.311. S). .3.46 (1H, d. J = 17.2 Hz). .3.6.3 (1H. D. = 17.2 Hz). 4.07 (211 ni), 5.06 (1H, d, J = 5.1 Hz), 5.6-5.9 (411 m). 7.20 (1H, d, J = 1.5 Hz), 8.24 (2H, s), 9.70 (1H, brs) 34 1750. 1660, 1620. 1580 (DMSO-tl _{6) 2..3-.3.4} (12H. M), 2.97 (.31-1. S). .3.44 (1H, d, J = 17.2 Hz), .3.62 (1H, d, J = 17.2 Hz), 4.07 (2H, brs), 5.05 (1H, d, J = 4.8 Hz), 5.6.3 (2H , m), 5.78 (2H, d, J = 55.5 Hz), 7.20 (1H, d, J = 15.4 Hz), 8.21 (2H, s), 9.69 (1H, d, J = 8.8 Hz) 35 1750. 1660, 1620, 1590 (DMSO ~ d ₆ ) .3.4-.3.8 (611. ni). 3.9-4.05 (4H, m), 4.15 (1H, d, J = 16.1 Hz), 4.20 (1H, d. J = 16.1 Hz). 4..37 (1H, d, J = 7.3 Hz), 5.08 (1H, d, J = 4.7 Hz). 5.65-5.8 (211. m). 5.79 (2H, d, J = 55.3 Hz), 7.1.3 (1H, d. J = 15.7 Hz). 8.21 (.311 s), 8.24 (1H. S), 9.70 (1H, d, J = 8.1 Hz) 36 1750, 1650, 1610. 1590 (DMSO-d ₆ ) 3.2 -3.3.6 (1 OH. Ni). .3.8-4.0 (4H. Ni). 4.1-4.3 (2H, ni). 5.11 (1H, d. 1 = 4.7 Hz). 5.80 (2H. D .1 = 62.0 Hz). 5.80-5.95 (2H, m), 7.12 (111, d. 1 = 16.0 Hz). 8.21 (2H, s) 37 (D ₂ O) 3.65-3.82 (8H, ni), 4.20-4.35 (6H. Ni), 4.38-4.50 (2H, ni), 5.41 (1H, d. 1 = 4.8 Hz). 5.98 (2H, d. J = 54.6 Hz). 5.99 (1H, d, J = 4.8 Hz), 6.00-6.10 (1H, m), 7.08 (111, i.e. J = 15.8 Hz) 38 (D, O) .3.55-3.90 (1 OH, ni). 4.14-4.24 (4H, ni), 4.35-4.55 (.311. Ni). 5..38 (1H. D. 1 = 4.8 Hz), 5.97 (1H. D. 1 = 4.8 Hz). 5.96 (2H. D. 1 = 54.22 Hz). 5.95-6.05 (1H. Ni). 7.07 (1H, d, 1 = 15.3 Hz) 39 (DMSO-d 6) 1.14 and 1.16 (total .31-1, d, J = 6.6 Hz), .3.2 -3.7 (8H, m). .3.85-4.00 (411. ni), 4.2-4.45 (.311. Ni). 5.05 and 5.06 (total 1H, d, 1 = 4.8 Hz). 5.6-5.7 (2H, m), 5.75 (211, d. 1 = 55.3 Hz), 7.18 and 7.20 (total IH. d. 1 = 15.8 Hz). 8.2.3 (2H, s), 9.67 (1H, d, J = 8.4 Hz) 40 1760, 1660, 1590, 1520 _(DMSO-d6) 1.95-2.0.3 (4H, m), 2:40 (1H, singlet m), .3.4-4.8 (4H, m), 4:00 to 4:05 (2H, m), 4.25 (2H. Ni). 5.05 (1H, d, J = 4.8 Hz), 5.6-5.8 (2H, ni). 5.79 (2H, d. 1 = 55..3 Hz), 6.99-8.29 (4H, in). 7.14 (1H, d, J = 16.0 Hz), 8.22 (2H, s), 9.70 (1H, d, J = 8.1 Hz) 41 1750, 1660. 1580 _(DMSO-d6) 1.73 (3H, s), 1.95 <6H, m), .3.41 (6H, m), 3:47 (lH, d, J = 9.16 Hz). .3.64 (1H. D, J = 1.6.9 Hz), .3.89 (2H, brs). 5.08 (1H, d, J = 4.8 Hz). 5.66 (1H, dd, J = 4.8 Hz, 8.4 Hz), 5.70 (1H, m), 5-79 (2H, d, J = 55.1 Hz), 7.14 (111, d, J = 15.8 Hz), 8.21 ( 2H, s). 9.70 (1H, d, J = 8.4 Hz). 10.7.3 (IH.s) 42 1750. 1650, 1580 (DMSO-d _fi) 2.61 (2H, brs), .3.6.5-.3.2 (4H, m), 3:47 (1H, d,> 2.17 Hz). .3.69 (1H. D. = 17.2 Hz). .3.87 (2H. T. J = 4.8 Hz). 4.0-4.2 (4H. M). 5.07 (1H, d. J = 5.1 Hz). 5.60-5.85 (1H. Ni), 5.66 (1H. Dd. 1 = 5.1 Hz, 8.1 Hz). 5.79 (2H, d, J = 5.3.1 Hz), 6.08 (1H, s), 7.18 (1H, d, J = 15.8 Hz), 7.85 (1H, s), 8.21 (2H, s), 9.70 (1H .d, 1 = 8.1 Hz) 43 1750, 1660, 1580 _(DMSO-d6) 2.61 (2H, s) .3.2-.3.7 (4H. Ni). .3.47 (1H, d, J = 17.6 Hz), .3.67 (1H, d, J = 17.6 Hz), .3.87 (211 m). 4.08 (4H, m). 5.06 (1H, d, J = 5.1 Hz). 5.40-5.90 (211 ni) .5.66 (1H.dd, 1 = 5.1 Hz, 8.1 Hz), 5.79 (2H, d. 1 = 58.6 Hz), 6.48 (1H, s). 7.19 (1H, d. J = 18.0 Hz). 7.21 (1H, s). 7.61 and 7.67 (total IH. S). 8.22 (2H, s). 9.69 and 9.71 (total 1H. D, 1 = 8.1 Hz) 44 1760, 1660, 1600, 1520 _(DMSO-d6) 1.24 (311, t, 1 = 7.2 Hz). 2.94 (3H, s), 3.29 (4H, brs), .3.45 (1H.d. 1 = 16.9 Hz), .3.65 (1H. D. J = 16.9 Hz), .3.8.3 (2H, brs), 4.00 (2H. Brs). 5.06 (1H, d, J = 4.8 Hz), 5.6-5.75 (2H, ni), 5.78 (2H, brd, J = 55.5 Hz). 7.17 (111 d 1 = 15.8 1 Iz), 8.24 (211 s), 9.70 (111 d, 1 = 8.0 Hz)

HU 207 088 B

Number of example IU specimens <cm ' ¹ New) Nuclear Magnetic Resonance Spectrum (OH) 45 1760. 1660. 1600. 1520 (D 0) 1.55 (3H, t. J = 7.3 Hz). 3.32 (314s). 3.71 (2H, q, J = 7.3 Hz). 3.78 (114th J = 17.2Hz). 3.83 (1H. Cl. J = 7.2 Hz). 4.32 (2H, brd, J = 7.3 Hz). 4.72 (214, s). 5.41 (1H, d, J = 4.8 Hz). 5.97 (2H. Cl. J = 54.5 Hz). 5.99 (1II, that is, J = 4.8), 6.0-6.1 (1H, m), 7.14 (1I, cl. J = 15.4 Hz) 46 1750. 1660.1590. 1520 (DMSO-t ₆ ) 3.10-3.87 (4H. Ni). 3.17 (3H, s). 3.49 (1H.d. J = 17.2 Hz). 3.68 (1H, d. J = 17.2 Hz), 4.09 (2H, s). 4.26 (214, d. J = 7.0 Hz), 5.08 (1H, d, J = 4.8 Hz), 5.6-5.9 (3H, m). 5.67 (1H, dd. J = 4.8 Hz, 8.4 Hz). 7.14 (1H, cl. J = 15.3 Hz). 7.62 (I H. s). 8.17 (1H, s). 8.22 (2 H, s). 9.72 (1H.d.1 = 8.4 Hz) 47 1750. 1650. 1600. 1510 _(DMS0-d6) 3.10 and 3.12 3H doped. s). 3.53-3.92 (8 H, m). 4.33 (2H, m), 5.18 (1H, d, J = 4.8 Hz). 5.79 (2H, d, J = 57.2 Hz). 5.80 (1H, dd. J = 4.8 Hz, 8.4 Hz). 6.03 (1H, m). 7.01 (1H. D, J = I5.8 Hz), 8.22 (2H. S), 9.79 (1H.d. J = 8.4 Hz) 48 1765. 1680, 1595. 1525 (DMSO-d ₍₁ ) 3.27 (3H, s). 3.50 (1H, d, J = 17.6 Hz). 3.69 (1H, d, J = 17.6 Hz). 4.28 (411 s). 4.37 (2H. m) 5.09 (111 d. J = 4.8 Hz), 5.68 (1H. dd. 1 = 4.8 Hz. 8.4 Hz), 5.74 (1H. m). 5.79 (2H. d, 4 = 55.3 Hz), 7.14 (1H. D. J = 15.4 Hz). 7.66 (214 s). 8.11 (114 s). 8.14 (114 s). 8.22 (2H. S), 9.72 (111 d. J = 8.4 Hz) ) 49 1765. 1670. 1595. 1510 _(DMSO-d6) 2.63 (2H. Ni). 3.2-3.7 (4H, ni), 3.73 (1H, d, J = 16.9 Hz). 3.84 (4H, s). 4.07 (211 ni), 5.07 (1H, d. J = 4.8 Hz). 5.43 (1H, in). 5.60 (1H. Cld. J = 4.8 Hz. 8.1 Hz). 5.73 (1H, ni), 5.80 (214 d, J = 54.6 Hz). 7.06 (1H. S). 7.20 (1H. Cl. .1 = 15.8 Hz). 7.89 (114, s). 8.21 (214, s), 9.52 (1H.d.1 = 8.1 Hz) 50 1750. 1650. 1610, 1580 (D ₂ O) 1.33 and 1.35 (total 314 cl. 1.1 = 6.2 Hz). 3.50-3.65 (2H, m), 3.65-3.85 (614. ni). 4.1-4.2 (4H. Ni). 4.3-4.55 (214. in). 4.55 (1H. In). 5.38 (111, d J = 4.7 Hz). 5.95 (211 d .1 = 54.1 Hz). 5.97 (1H. D, .1 = 4.7 Hz), 6.02 (111. in). 7.02 (1H d. J = 15.8 Hz) 51 (D ₂ O) 2.09 (314 s), 3.55-3.85 (10H. Ni). 4.15 (414, brs), 4.32 (214, d. J = 7.7 14 /.). 5.38 (114 d, J = 4.7 Hz), 5.95 (214 d, J = 55.0 Hz), 5.97 (114 d, J = 4.7 Hz). 6.05 (114. in). 7.05 (1H. Cl. J = 15.7 Hz) 52 1750. 1720. 1650. 1580 (DMSO-d ₆ ) 2.5-3.5 (21H, ni), 3.64 (1H, d, J = 16.9 Hz), 4.11 (214, d 4 = 6.6 Hz). 5.07 (1H, d, J = 5.1Hz), 5.6-5.9 (3H, ni), 5.65 (1H, dd, 4 = 5.1Hz, 8.4Hz), 7.16 (114th cl. 4 = 15.8Hz). 8.21 (214 s), 9.74 (1H, Cl. 4 = 8.4 Hz) 53 1750. 1660. 1610. 1580 (D ₂ O) 3.46 (314. s). 3.50 (3H, s). 3.63 (214, s), 4.2-4.6 (2H, in). 5.21 (114th cl. 4 = 6.0 Hz). 5.78 (114th Cl. 4 = 6.0 Hz), 5.78 (214d. 4 = 60.0 Hz). 5.80 (II I, m). 6.85 (1H.d, 4 = 17.0 Hz) 54 (DMSO-d _h) 3:32 (614 s). 3.54 (1I I. d, 4 = 17.5 Hz). 3.75 (1H, d, J = 17.5 Hz), 4.44 (211 ni). 5.15 (111 d .1 = 4.6 Hz). 5.7-6.0 (3H, m), 7.16 (1H, d. 4 = 15.4 Hz). 8.21 (214s). 9.76 (114 d. 4 = 8.8 Hz) 55 1760, 1670, 1640. 1590. 1520 _(DMSO-d6) 2.64 (314 d. .1 = 4.4 Hz). 3.13 (3H, s). 3.16 (3H, s), 3.48 (111 d, 4 = 17.2 Hz), 3.65 (114, d, 4 = 17.2 Hz), 4.03-4.18 (414, ni), 5.07 (1H.d. = 4.8 Hz) ). 5.64-5.84 (Hl. M). 5.66 (1H, dd. J = 4.8 Hz, 8.4 Hz), 5.78 (214 Cl. 4 = 56.4 Hz), 7.17 (114 d. J = 15.4 Hz). 8.23 (2H, s), 9.19 (1 H (? J = 4.4 Hz). 9.71 (114 d. 4 = 8.4 Hz.) 56 1760. 1650. 1600. 1520 (DMSO-d ₆ ) 2.88 (314 s). 2.94 (314s). 3.15 (6H, s), 3.45 (1H, d, 4 = 16.9 Hz), 3.63 (114, d, 4 = 16.9 Hz). 4.20 (214, d. 4 = 7.7 Hz), 4.34 (2H, s), 5.05 (111 d .1 = 5.1 II /.), 5.6-5.7 (1II. Ni), 5.63 (114, dd, 4) = 5.1 Hz. 8.1 Hz). 5.71 -5.85 (211. m). 7.14 (111 d .1 = 15.8 Hz). 8.24 (2H, s). 9.70 (III. Cl. .1 = 8.1 Hz) 57 1765,1670.1600.1520 (D, O) 1.87 (614. s). 3.18 (6144 s), 3.78 (114 Cl. 4 = 17.5 Hz). 3.84 (1 H d. J = 7.5 Hz). 4.26 (214, d .1 = 7.3 Hz). 5.40 (1H, d, 4 = 4.8 Hz), 5.97 (2H, d, J = 54.2 Hz), 5.98 (Cl, 114 = 4.8 Hz). 6.08 (1 H. dd. 4 = 15.8 Hz, 7.3 Hz). 7.03 (114d, .1 = 15.811 /.) 58 1765, 1665, 1600. 1525 (DMSO-d _ft) 1:46 (3H, cl. .1 = 6.6 I-lz). 2.64 (314, cl. 4 = 4.8 Hz), 3.04 (3H, s), 3.08 (314 s). 3.50 (1H, cl. 4 = 17.0 Hz), 3.65 (1H, d, J = 17.0 Hz), 4.0-4.2 (214, ni), 4.25-4.35 (III, in), 5.08 (1H, d, 4 = 5.0 Hz), 5.66 (4H, dd, J = 5.0 Hz, 8.0 Hz), 5.7-5.8 (114, ni), 5.78 (2H, d, J = 55.0 Hz), 7.17 (1H.d, 4 = 15.4 Hz) ), 8.22 (214, s), 9.13 (114, brs), 9.73 (1H, d, 4 = 8.0 Hz)

HU 207 088 B

Example number IR spectrum (cm + Nujol) Nuclear Magnetic Resonance Spectrum (8) 59 1765. 1670, 1600, 1525 _(DMS0-d6) 1:44 (3H, d. J = 7.0 Hz), 2.65 (3H, d, J = 4.5 Hz), 3.00 (3H, s). 3.06 (3H, s). 3.50 (1H, d, J = 17.0 Hz). 3.68 (1H, d, J = 17.0 Hz), 3.9-4.0 (1H, m). 4.3-4.5 (2 H, m). 5.11 (1H, d, J = 4.8 Hz), 5.65-5.80 (2H, m). 5.78 (2H, d, J = 55. () Hz), 7.26 (1H, d, J = 5.4 Hz), 8.21 (2H, s), 9.71 (1H, d, J = 8.0 Hz), 9.79 (1H , brs) 60 1760. 1670. 1595. 1515 _(DMSO-d6) 2.77 (2H. M). 3.03 <6H. s), .3.48 (1H, d, J = 16.9 Hz). 3.66 (1H, d. J = 16.9 Hz), 4.10 (2H, in). 4.26 (1H, d, J = 7.7Hz), 5.08 (1H, d, J = 4.8 in 1). 5.66 (111 dd. J = 4.8 1 Hz, 8.4 Hz). 5.76 (1H, ni). 5.79 (2H, d. J = 55. () Hz). 7.14 (1H. S). 7.20 (1H. D. J = 15.8 Hz), 7.82 (2H, s), 8.22 (2H, s), 8.27 (1H, s), 9.72 (1H.d. J = 8.4 Hz) 61 1765,1675,1595.1525 _(DMSO-d6) 2.77 (2H, m), 3:02 (3H, s). 3.03 (3H, s), 3.49 (1H, d, J = 16.9Hz), 3.62 (1H, d, J = 16.9Hz), 4.10 (2H, ni), 4.32 (1H, d, J = 7.7Hz), 5.09 (1H, d, J = 5.1 Hz). 5.66 (1H, dd, J = 5.1 Hz, 8.1 Hz), 5.75 (1H, m), 5.79 (2H, d, J = 56.8 Hz). 7.16 (1H, d, J = 15.0 Hz), 7.18 (1H, s). 7.71 (1H, s). 7.83 (1H, s), 8.22 (2H, s), 8.33 (1H, s), 9.72 (1H, d, .1 = 8.1 Hz) 62 1765. 1680. 1590. 1525 (DMSO-d ₆ ) 3.07 (311 s). 3.14 (3H, s). 3.47 (1H, d, J = I6.9 Hz). 3.67 (1H, d. J = 16.9 Hz). 3.86 (1H. Dd. J = 5.9 Hz). 4.01 (1H, t. J = 5.9 Hz). 4.08 (111d d. .1 = 5.9 Hz. 12.1Hz). 12.1 Hz). 4.18 (2H, ni), 5.07 (1H, d, J = 5.1 Hz). 5.67 (1H.dd. J = 5.1 Hz, 8.1 Hz), 5.76 (1H. Ni), 5.78 (2H, d, J = 55.2 Hz). 7.13 (1H, d. J = 15.8 Hz), 7.76 (1H, s), 8.22 (2H, s), 8.33 (111, s), 9.70 (1H.d, J = 8.1 Hz) 63 _(DMSO-d6) 3.17 (3H. S). 3.18 (3H.s). 3.47 (1H, d, J = 17.0Hz), 3.67 (1H, d, J = 17.0Hz), 3.85-3.95 (1H), 3.95-4.10 (2H, m), 4.10-4.25 (2H. In) ), 4.35-4.45 (1H, in), 4.75-4.85 (1H, m), 5.08 (1H, d, J = 4.8 Hz). 5.67 (1H. Dd. J = 4.8 Hz, 8.0 Hz), 5.70-5.85 (1H, ni), 5.79 (2H, d, J = 55 Hz.) 7.05 (11-1.d, J = 15.4 l- lz), 8.21 (2H.s) .9.31 (1H, brs), 9.71 (tll.d, J = 8.0 Hz) 64 (DMSO-d ₆ > 3.01 (611, s), 3.2-3.5 (211 ni), 3.46 (1H, d, J = 16.9 Hz), 3.64 (1H, d. J = 1.6.9 Hz), 3.84 ( Br 211) 4.03 (2H, d. J = 7.3 Hz), 5.06 (1H, d. J = 4.8 l-lz), 5.50-5.75 (III. Ni), 5.64 (1H, dd, J = 4.8 Hz) , 8.1 Hz), 5.78 (2H, d. J = 55.1 Hz), 7.16 (1H, d. J = 15.8 Hz), 8.24 (2H, s), 9.71 (111 d. J = 8.1 Hz) 65 1765, 1660, 1600, 1525 (DMSO-tl ₆₎ II 1 (3H. D, J = 6.2 Hz). 3.01 (3H, s), 3.04 (3H, s), 3.22 (211 brd. J = 7. () Hz). 3.46 (1II. D .1 = 17.0 Hz), 3.65 (111, d, J = 17.0 Hz). 4.06 (2H, brd, J = 6.2 Hz), 4.26 (1I, I. brs). 5.06 (1H, d, J = 5. () Hz), 5.6-5.75 (2H, ni), 5.79 (2H, brd, J = 55.3 Hz), 7.16 (1H, d, J = 15.8 Hz), 8.27 (2H, s), 9.71 (1H, d, J = 8. 1 Hz.) 66 1765. 1660, 1600, 1525 _(DMSO-d6) II 1 (3H, d. J = 6.2 Hz). 3.01 (3H, s), 3.04 (3H, s), 3.22 (2H. Brd, J = 7.0 Hz). 3.46 (1H, d, J = 17.0 Hz), 3.63 (1H, d, J = 17.0 Hz). 4.06 (2H, brd, J = 6.2 Hz), 4.26 (1II, brs), 5.06 (1H, d, J = 5.0 Hz), 5.6-5.75 (2H, m), 5.79 (2H, brd, J = 55.3 Hz) ), 7.16 (1H, d, J = 15.8 Hz). 8.27 (2H.s) .9.71 (1H.d. J = 8. 1 Hz) 67 1765, 1670. 1600, 1530 (DMSO _d-f, J 1:32 (3H, d. J = 6.6 Hz), 2.93 (31-1, s), 2.98 (3H, s), 3.4-3.5 (1H. M), 3:46 (1H. D. J = 17.0 Hz), 3.64 (1H, d, J = 17.0 Hz), 3.65-3.85 <2H, ni), 4.04 (2H, d, J = 7.3 Hz), 5.06 (1H, d, J = 5.0 Hz) , 5.6-5.8 (2H. Ni). 5.79 (211, d. J = 55. () Hz), 7.18 (1H, d, J = 15.8 Hz). 8.23 (2H, s), 9.70 (1H, d. J = 8. () 1-1z) 68 1765. 1670. 1600. 1525 _(DMSO-d6) 1:32 (311, d, J = 6.6 Hz), 2.93 (3H, s), 2.96 (3H, s), 3.4-3.5 (111, 111), 3:45 (1H, d, J = 17.2 Hz), 3.65 (11II, d, J = 17.2 Hz), 3.7-3.8 (211 ni). 4.07 (2H, ni), 5.06 (1H, d, J = 5.0 Hz), 5.6-5.75 (2H, ni), 5.78 (2H, d, J = 55.0 Hz). 7.16 (1H.d. J = 15.8 Hz), 8.24 (2H. S), 9.70 (1H, d. J = 8.4 Hz) 69 1760. 1660, 1595. 1520 _(DMSO-d6) 1:36 (6H, s), 2.88 (6H. S). 3.47 (1H, d, J = 17.0 Hz), 3.63 (1H.d. J = 17.0 Hz). 3.70 (2H, s), 4.00 (2H, d, J = 7.3 Hz). 5.06 (1H, d. J = 5.0 Hz). 5.64 (11, dd. J = 5. () Hz, 8.4 Hz), 5.65-5.75 (1H, 111). 5.79 (brd. 211 J = 55.0 Hz). 7.14 (111 d. J = 15.4 Hz), 8.22 (2H, s). 9.70 (1H, d, J = 8.4 Hz)

HU 207 088 B

Example number _ IR spectrum (cm''Nujoi) Nuclear Magnetic Resonance Spectrum (6) 70 1760,1670,1595,1525 - (DMSO-d _ft ) 3.12 (614. s). 3.91 (6H, s). 3.49 (1H, d.) =) 7.2 Hz), 3.67 (1H, d.) = 17.2 Hz). 4.35 (2H, m), 5.08 (11-14, cl, J = 5.1 Hz), 5.66 (1 H dd. J = 5.1 Hz, 8.4 Hz). 5.7-6.0 (1 H. ni). 5.79 (214, d, J = 55.5 Hz), 7.09 (1H.d.) = 15.8 Hz). 8.21 (211s). 9.71 (114, (1,) = 8.4 Hz) 71 1750.1660. 1590 (D _? O) 3.16 (614, s), 3.62 (214, s). 3.68 (314, s). .3.81 (2H, s), 4.15 (2H. Ni <5.19 (1H. Cl.) = 5.5 Hz). 5.76 (211 d .1 = 60.0 Hz). 5.78 (1.14 cl.) = 5.5 Hz). 5.90 (1 H. ni). 6.84 (1.14 cl. J = 17.0 Hz) 72 1750. 1660. 1580 (DMSO-d ₆ ) 3.15 (314 s), 3.21 (311 s). .3.47 (1H, cl,) = 17.2 Hz). 3.68 (d. 114) = 17.2 Hz). 3.77 (1H, d. J = 14.3 Hz). 3.9.3 (i. 14 d, J = 14.3 Hz), 4.12 (211. m). 5.08 (1H. D..1 = 4.8 Hz). 5.68 (1H, dd,) = 4.8 Hz, 8.1 Hz), 5.75 (1H, ni). 5.79 (2H, Cl,) = 55.3 Hz), 7.03 (1H, d, J = 15.8 Hz), 8.21 (2H, s), 9.72 (1H.d, J = 8.4 Hz), 11.4 (1H, brs). ) 73 1750, 1650. 1580 _(DMSO-d6) 3.14 (3H. S). 3.15 (314, s). 3.48 (1H. D. J = 16.9 Hz), 3.66 (1H.d, J = 16.9 Hz). 3.71 (2 µl. Cl. 4 = 5.9 Hz), 4.08 (214, in), 4.15 (2H, ni). 5.07 (1H. D. J = 5.1 Hz). 5.67 (111 dd, J = 5.1 Hz, 8.1 Hz), 5.70 (1H, ni). 5.78 (2H. Cl. J = 53.8 Hz). 7.07 (111s), 7.15 (1HCl, J = 15.8Hz). 7.54 (1H. S). 8.21 (214s). 9.15 (114, brs), 9.71 (1H, cl,) = 8.1 Hz) 74 I76Í). 1650. 1620. 1590, 1520 (DMSO-cl _ft ) 3.10 (314. s). 3.1-3.7 (8H. Ni), .3.22 (314, s), .3.41 (IH.d, .1 = 17.2 1?). .7.67 (1 14. d .1 = 17.2 Hz), 4.06 (214. ni). 4.35 (214 d, J = 6.2 Hz). 5.05 (1H, cl. 1.1 = 5.1 Hz). 5.6-5.9 (1II, ni), 5.66 (1H, dd, J = 5.1 Hz, 8.4 Hz). 5.78 (214 d. J = 55.3 Hz). 6.92 (1H, d .1 = 15.8 Hz), 8.20 (2H, s). 9.78 (1H.d, .1 = 8.4 Hz) ^{75 75} 1 1750, 1650, 1580, 1520 (DMSO-d (,) 3.13 (311 s). 3.13-3.50 (414, m). 3.16 (3H, s), .3.48 (1H. D.) = 16.9 Hz). 3.64 (1H. D..1 = 16.9 Hz). 4.00 (214s). 4.13 (214, cl. ) = 7.3 Hz), 5.06 (114th Cl. J = 5. T Hz). 5.6-5.9 (l H. ni). 5.66 (1H. Dd. .1 = 5.1 Hz. 8.1 11 /) 5.78 (211 d .1 = 55.3 Hz), 7.10 (1H, d, J =! 5.4 Hz), 8.22 (21-1. S). 8.96 (1H.d.) = 5.1 Hz). 9.71 (11, d, J = 8.1 Hz.) 1 I ⁷⁶ 1750, 1650, 1590, 1510 <DMSO-d ₍₁ ) 3.06 (614 s). .7.14-3.48 (2H. Ni). 3.19 (314, s), .7.22 (314, s). .3.66-7.75 (411. m). 4.09 (214. ni). 4.11 -4.70 (214 in), 5.07 (1H, d,) = 4.8 (10). 5.67 (Hd. Dd .1 = 4.8 Hz. 8.1 Hz), 5.71-5.77 (114, m), 5.79 <214. d. .1 = 55.0 Hz). 7.19 (1 14. d .1 = 15.4 Hz), 8.23 <214. s). 9.73 (1H, d .1 = 8.1 Hz) ί 77 1750. 1660. 1580 (DMSO-d _ft ) 1.98 (214 brs), 2.67 (614, s). 2.72 (214th brs). 3.00 (3H, s). 3.11 <3H. s). .7.20 (214. ni). 3.54 (1H d. J = 17.6 Hz). 3.82 (1H, d, J = 17.6 Hz). 4.03 (214 m). 5.15 (11 II, cl. 1.1 = 4.8 Hz.), 5.78 (1H, dd,) = 4.8 Hz, 8.1 Hz). 5.79 (2H, d, J = 54.9 Hz), 5.91 (1H, ni), 7.09 (114, d,) = 15.4 Hz). 8.22 (211s), 9.71 (Hl.d,) = 8.1 Hz) 78 1750, 1660, 1580 _(DMSO-d6) 2:48 (6H. S). 2.60 (214 ni), .3.07 (3H, s), 3.08 (3H. S), 3.24 (214 ni). 3.54 and 3.59 (total 1H, d, J = 17.6 Hz), 3.82 and 3.88 (total 1H, cl, J = 7.6 Hz). 4.15 (211 m). 4.38 (1H, ni). 5.17 and 5.18 (total 14d) = 4.8Hz), 5.79 (1H), 5.79 (214, cl, J = 57.1Hz), 6.00 (1H, ni), 7.03 and 7.07 (total 114 . cl. J = 1 5.8 Hz). 8.22 (2H, s). 9.74 and 9.77 (total 1H. D. J = 8.4 Hz) 79 1 ! 1750, 1650. 1580, 1510 (DMS0-d _ft ) 3.50 (Dec. 14 .1 = 16.9 Hz). .3.68 (1H. D. 4 = 16.9 Hz.), 4.45-5.11 (14H. In). 5.07 (111. (1..1 = 5.1 Hz), 5.63-5.71 (114, m), 5.65 (111 dd. J = 5.1 Hz. 8.1 Hz). 5.78 (2H. D.) = 58.3 Hz). 7.17 (1H, d, J = 15.8 in 1). 8.27 (211, s), 9.72 (1 I id. 1 = 8.1 Hz) <80 ! (D, 0) 3.69-3.74 (211. ni). 5.13 (211 cl. .1 = 4.8 Hz). 5.37 (1 II, d, J = 4.8 j 11 / j. 5.96 (III. D. 1 = 4.8 11 z), 5.96 (211 cl. J = 54.2 Hz). 6.18 (1 H. ni). &Gt; 6.92 (1H, cl. J = 15.8 Hz). 7.54-7.56 (1II. M), 7.63-7.66 (1H, in), ß 7.87-7.89 (214 ni)  81 I t 1750. 1650. 1580. 1510 (DMSO-d _(l ) 2.41 (.711. S). 3.02 (211 vol. ₁ = 5.5 Hz). 3.42 (114, d, J = 17. 1! /). 3.52 (111 d. 1 = 17 Hz) 3.62-3.66 (214, ni), 5.03 (111 d,) = 4.8 11 /) 5.21 (2H.d.1 = 5.1 Hz). 5.6.3 (Η 1st dd .1 = 4.8 Hz. 8.4 Hz). ; 5.71-5.84 (1H. Ni). 6.67 (11-1. Cl, .1 = 16.1 Hz). 8.24 (2), the fourth s), 9.68 (ΙΉ.d, J = 8.4Hz), 10.1 (1H, s)

HU 207 088 Β

Example number IR spectrum (cm 'Nujol) Nuclear Magnetic Resonance Spectrum (8) 82 - (DMSO-d 6) 3.39 (1H, d, > 16.9 Hz), 3.49 (III, d, > 16.9 Hz), 4.2-4.35 (2H. Ni), 5.04 (III. Cl.> 5.0 Hz). 5.15-5.40 (2H, ni), 5.65 (1H, dd.> 5.0 Hz, 8.2 Hz). 5.75-5.90 (1H. Ni), 5.77 (2H, cl, J = 56.4 Hz), 7.11 (1H, cl,> 15.8 Hz), 7.45 (1H, s). 8.0-8.15 (2H, ni), 8.22 (2H, s), 8.30 (1H, s). 8.54 (1H, m). 9.03 (1H, cl, J = 5.5 Hz), 9.68 (1H, cl,> 8.2 Hz) 83 1760. 1670, 1620, 1520 (DMSO-d 6) 3.2-3.7 (10H. Ni). 5.01 (1H, cl, > 4.8 Hz), 5.37 (2H, cl, > 4.5 Hz). 5.62 (1H, dd,> 4.8 Hz, 8.2 Hz), 5.78 (2H, cl,> 56.4 Hz), 5.98 (1H, clt.> 4.5 Hz, 16.5 Hz). 6.29 (111, Cl, > 16.5 Hz), 8.17 (2H, d, > 7.0 Hz), 8.21 (2H, s), 9.06 (2H, d, > 7.0 Hz), 9.69 (1H, d, > 8.2 Hz) 84 1765, 1660, 1600, 1520 (DMSO-d _h) 3.30-3.60 (8H, m), 5:04 (1H. D,> 4.8 Hz), 5:35 (2H, d,> 6.6 Hz). 5.64 (1H, el,> 4.8 Hz, 8.4 Hz), 5.78 (2H, cl,> 56.0 Hz), 5.80-5.96 (1H, m). 7.20 (1H, d, > 15.8 Hz), 8.23 (2H, s), 8.46 (2H, d, > 6.6 Hz). 9.18 (2H, cl,> 6.6 Hz, 9.56 (1H, cl,> 5.0 Hz), 9.71 (1H, d,> 8.4 Hz) 85 1760. 1665,1590, 1520 (DMSO-d ₍ ,) 3.41 (1H, Cl, > 17.0 Hz). 3.48 (1H, Cl, > 17.1) Hz), 3.74 (211 s). 5.04 (1H. Cl.> 5.0 Hz). 5.30 (2H. D.> 7.3 Hz), 5.63 (1H, el.> 5.0 Hz. 8.4 Hz). 5.77 (2H. Cl.> 54.2 Hz). 5.80-5.90 (1H, m), 7.19 (1H, s). 7.24 (11-1. Cl.> 15.8 Hz). 7.82 (1H, s). 8.09 (1H. Dd,> 6.2 Hz, 8.0 Hz), 8.23 (211 s). 8.46 (1H, cl. &Gt; 8.0 Hz), 8.93 (1H, cl, > 6.2 Hz), 8.98 (1H, s). 9.71 (1H, d, > 8.4 Hz) 86 1765. 1670.1595. 1525 (DMSO - _d6) 3:42 (IH, cl,> 9.16 Hz), 3:56 (IH, d,> 9.16 Hz), 4.19 (2H ni.), 4:41 (2H, m.). 4.98 (2H.s). 5.04 (111, d, > 4.8 Hz), 5.18 (2H, d, > 6.6 Hz). 5.63 (1H.dd.> 4.8 Hz), 5.77 (1H, m), 5.78 (211, cl,> 52.0 Hz). 6.77 (1H, cl, > 2.9 Hz). 7.6 (1II, cl.> 15.8 Hz), 8.21 (2H, s). 8.48 (1H. Cl.> 2.9 Hz). 9.69 (1H. Cl. .1 = 8.4 Hz) 87 (D, O) 2.93 (3H, s). 3.26 (6H, s), 3.6-3.9 (6H, m), 4.22 (2H, d, > 7.3 Hz '). 5.40 (1H, cl.> 4.8 Hz). 5.97 (211 cl. 1 = 54.2 Hz), 5.98 (11-1, cl, J = 4.8 Hz). 6.1X1-6.15 (111. ni). 7.07 (1H, cl. 1 = 15.4 Hz) 88 1750, 1650.1590, 1525 (DMSO-d _ft ) 3.02, 3.04. 3.06 and 3.08 (toluene 6H, s), 3.20-3.50 (6H, m), 3.61 and 3.70 (total 1H, d.> 16.9 Hz), 4.06-4.13 (3H, m), 5.05-5.75 (1H. Ni) . 5.06 and 5.07 (overall 1H, cl, > 4.8 Hz), 5.65 (1H, >> 4.8 Hz, 8.1 Hz), 5.78 (2H, cl, > 55.3 Hz), 7.09 and 7.14 (tolal, 1H, d, > 15.8) Hz). 8.21 (2H, s), 9.71 and 9.74 (total 1H, d, &gt; 8.4 Hz). 89-1 1755, 1650, 1590, 1525 _(DMSO-d6) 1.75 (IH, m), 2:51 (IH. M), 3:04 (3H, s), 3.2-3.9 (7H); 4.03 (1H, m). 4.19 (1H, ni), 4.46 (1H, s), 5.05 (1H, d, > 4.8 Hz), 5.6-5.8 (1H, m). 5.63 (1H, dcl, > 4.8 Hz, 8.1 Hz), 5.78 (2H, d, > 58.6 1 Iz). 7.15 (1H, d.> 15.8 Hz), 8.21 (2H. S), 9.69 (1H, d.> 8.1 Hz) 89-2 1755, 1650, 1590, 1525 (DMSO-d 6) 1.80 (1H. Ni). 2.60 (1H, ni). 3.03 (3H, s), 3.48 (1H, cl. > 16.9 Hz). 3.62 UH. cl. &Gt; 16.9 Hz), 3.65-4.00 (6H, ni), 4.16 (1H, ni), 4.46 (1H, s). 5.07 (11II d.> 5.1 Hz), 5.6-5.8 (1II, m), 5.65 (1H, dd,> 5.1 Hz. 8.1 Hz). 5.78 (211.d.J = 57.5 Hz). 7.17 (Ilid, > 15.8Hz), 8.22 (2H, s). 9.70 (1H, cl, > 8.1 Hz) 90 1760, 1650. 1590, 1530 (DMSO-d 6) 1.71 (2H, brs), 1.97 (211, brs), 2.94 and 2.96 (overall 3H, s), 3.1-3.5 (6H. Ni) .3.61 and 3.62 (total 1H, cl,> 17.2 Hz), 3.77 (1H, brs). 4.02 (2H. Ni). 5.04 and 5.05 (total 11II, d,> 17.2 Hz), 5.6-5.8 UH. ni), 5.63 UH.elei.> 5.1 Hz, 8.4 Hz), 5.79 (1H. d,> 58.6 Hz), 7.19 and 7.20 (total 1H, cl,> 15.4 Hz), 8.24 (2H, s), 9.69 (1H, cl,> 8.4 Hz) 91 1760. 1650. 1590, 1530 (DMSO-dft) 1.72 (brs 21-1). 1.99 (2H, brs), 3.2-3.8 (8H, m), 3.84 (3H, ni). 4.10 (21-1. M). 5.05 and 5.06 (tolal 1H, cl, ≥ 4.8 Hz), 5.6-5.8 (1H, m), 5.64 (11.0 I, ≥ 4.8 Hz, 8.1 Hz), 5.78 (2H, d,> 55.1 Hz), 7.18 UH.cl. > 14.3 Hz). 8.21 (2H, s). 9.69 UH, cl,> 8.1 Hz) 92 1760. 1665,1590, 1520 (DMSO-dft) 3.15 (311 s). 3.20 (3H, s). 3.47 (1H, cl, > 16.9 Hz), 3.66 (11II, cl, > 16.9 Hz). 4.05-4.25 (4H. Ni), 4.45-4.55 (1H, m), 4.60-4.70 011, ni). 5.06 (111. cl.> 4.8 1? 2), 5.66 (11-1, dcl,> 4.8 Hz. 8.1 Hz), 5.7-5.8 (1I I. ni). 5.78 (1H, cl, > 54.0 Hz), 7.09 (1H, cl, > 15.4 Hz), 8.22 (2H.s) .9.20 (1H, brs), 9.71 (1H.d,> 8.1 Hz)

HU 207 0X8 B

Example number IR spectrum (cm ^-1 Nujol) Nuclear Magnetic Resonance Spectrum (OH) 93 1760. 1660, 1595 _(DMSO-d6) 2.61 (2H, m), 2.96 (s 311). 2.97 (3H, s), 3.3-3.6 (2H. In), 3.45 (1H, (1. J = 16.9 Hz). 3.68 (1 H d. J = 16.9 Hz). 3.96 (2H. D, J = 7.3 Hz), 5.07 (1H.d, J = 4.8 Hz), 5.6-5.8 (1H, m), 5.65 (1H, dd, J = 4.8 Hz, 8.1 Hz) 5.78 (211 d, J = 58.3 Hz) ) 7.08 (111s) 7.18 (1H, d. J = 15.8 Hz) 7.82 (1H.s) 8.21 (2H. S) 9.70 (1 H d. J = 8.1 Hz) 94 i 176 (). 166 (). 159 (). 152 (1 _(DMSO-d6) 2:08 (2H. S). 2.98 (3H, s). 3.2-3.8 (1 OH. Ni). 5.07 (1H, cl, J = 4.8 Hz). 5.6-5.9 (Hl. M). 5.65 (1H. Dd, J = 4.8 Hz. 8.1 Hz), 5.79 (2H. D. J = 55.3 Hz). 6.05 (2H, s). 7.19 (1H.d. J = 15.8 Hz). 8.21 (2H, s). 9.70 (1H.d. J = 8.1 Hz) ⁹⁵ 1760. 1660. 1595, 1520 (DMSO- ₆ ) 3.02 (311 s). 3.04 (3H, s). 3.45 (1H, d, J = 17.2 Hz), 3.67 (1H, cl. J = 17.2 Hz), 3.7-4.0 (4H, ni). 4.15 (2H, ni), 5.07 (1H, d, J = 5.1 Hz). 5.65-5.80 (1H, m), 5.66 (1H, dd, J = 5.1 Hz, 8.1 Hz). 5.79 (2H. Cl, J = 55. () Hz). 7.15 (1H, d. J = 15.8 Hz), 8.21 (2H, s). 9.70 (1H, d, J = 8.4 Hz) 96 1760. 1665. 1595. 1520 _(DMSO-d6) 1.24 (6H. 1 .1 = 7.0 Hz). 3.2-3.6 (6H. Ni). 3.68 (1H. D .1 = 17.2 Hz). 3.90 (21-1. S). 4.09 (2 H, m). 5.07 (1 H d. J = 4.8 Hz). 5.6-5.8 (2H. Ni). 5.79 (211 d .1 = 58.6 Hz). 7.16 (1H, cl, J = 16.0 Hz), 7.69 (111 s). 8.08 (111s). 8.21 (211s). 9.70 (2H, d, J = 8.1 Hz) i _(DMSO-d6) 2.5-2.7 (2H. in). 2.57 (3H, d. J = 4.4 Hz). 2.97 (3H, s). ¹ 2.98 (311. s). 3.2-.3.6 (211. m). 3.45 (1H. (1..1 = 16.5 Hz), 3.71 (1H.d. 97 I 176 (). 1660.160 (). J = 16.5 Hz). 3.97 (211 s). 5.08 (111 .d J = 5.1 Hz) 5.65-5.80 (2H, m) i! 5.78 (211 d .1 = 55.0 Hz) 7.19 (111 d .1 = 15.4 Hz), 8.21 (21- 1. s), 8.42 (1H.brs). 9.72 (111, d, J = 8.4 1 z) 98 ; _(DMSO-d6) 2.84 (3H. S). 2.87 (2H. Ni). 2.97 (6H, s). .3.02 (3H. S). 3.46 (2H. ni). 3.46 (1H.d..1 = 17.2 Hz). 3.65 (1H. D. J = 17.2 Hz), 3.99 1760. 1660. 1600! (211, d, .1 = 7.3 Hz). 5.07 (1H, d. J = 4.8 Hz). 5.6-5.8 (1H, m), 5.64 (1H, dd. J = 4.8 Hz, 8.4 Hz). 5.78 (2H. D .1 = 58.6 Hz). 7.19 (1H. D, J = 15.4 Hz), 8.21 (21I.S). 9.70 (111, (1.1.1 = 8.4 Hz) 99 1760. 1660. 1595. 1525 _(DMSO-d6) 2.99 (6H. S). 3.32 (3H, s). 3.47 (2H. Brs). 3.48 (1H. Cl. J = 17.2 Hz). 3.65 (1H. D. J = 17.2 Hz). 3.76 (2H. Brs). 4.02 (2H.cl. J = 7 uHz). 5.07 (1H.d. J = 5.1 Hz). 5.6-5.7 (1H. In). 5.65 (1H, dd, J = 5.1 Hz, 8.4 1 Iz). 5.79 (211, cl. J = 55.7 in 1). 7.17 (111 d. J = 15.4 Hz), 8.21 (2H, s). 9.71 (1H.d.1 = 8.4 Hz) 10 (1 1760. 1670. 1590. 1520 (DMSO-cJ- _ft ) 1.20 (3H, d. J = 6.2 Hz). 3.06 (3H, s), 3.22 (3H, s), 3.48 (1H, cl. J = 17.0 Hz). 3.61 (1H, d. J = 17.0 Hz), 3.95 (1H, cl, J = 9.2 Hz). 4.15-4.45 (3H. Ni), 5.07 (111d. J = 4.X Hz). 5.66 (1H, dd, J = 4.8 Hz. 8.4 Hz), 5.79 (2H. Cl. J = 55. () Hz). 5.8-5.9 (1H, m). 7.01 (1H, Cl, J = 15.4 Hz), 7.83 (111, s), 8.21 (III, s). 9.71 (1H), J = 8.4 Hz) 101 1760. 1650, 1630. 1590 (DMSO-d _ft) 2.10 (2H. S). 3.30-3.90 (14H. In). 4.10-4.25 (2 H, m). 5.06 (111 d, J = 5.1 Hz), 5.6-5.8 (1 H. ni). 5.65 (1H. Dd, J = 5.1 Hz, 8.1 Hz). 5.78 (2H, cl. J = 58.6 Hz). 6.04 (2H, s). 7.17 (1H, cl, J = 15.8 Hz), 8.22 (211, s), 9.70 (1H.d,, 1 = 8.1 Hz.) δ (D ₂ O) 3.12 (6H, s), 3.78 (1H.d, J = 15.5 Hz), 3.85 (1H, d, J = 1.5.5 Hz), δ 4.11 (21-1, tl) .J-7.6 Hz), 4.60 (211, s). 5.40 (1H, d. J = 4.8 Hz), 5.97 (2H, 102 i 1760.1660.1590 λ cl. J = 54.6 Hz.). 5.98 (1H. D. J = 4.8 Hz.), 6.11 (1H. Dl. J = 7.6 Hz., 15.4 * i Hz). 6.66 (1H, d, .1 = 2.8 in 1). 7.04 (II I. d. J = 15.4 Hz), 7.93 (1H, d. J: .1 = 2.8 lys) ! _(DMSO-d6) 3.4-3.6 (2H. Ni). 5.03 (1H.d.J = 5.1Hz.), 5.1 () (1H.d. ,,,., ,, _7f , 1.1 = 7.0Hz), 5.64 (1H. Cici .1 = 5.1Hz. 8.0 Hz). 5.77 (2H. Cl, .1 = 55.32 Hz). 103 | 1750. 1660, 1620, 1590 5.70-5.9 (1 H. ni). 6.73 (2H, s). 7.21 (11I, cl. J = 15.7 Hz), 7.57 (1H, d. J = 1.8 Hz). 7.6-7.7 (1H.m). 8.05-8.15 (2H, m) 104 ; (l) ₂ O) 3.30 (311, s). 3.31 (311s). 3.77 (111 d, J = 17.0 Hz), 3.84 (1H.d., 1 = 17.0 Hz), 3.94 (2H, s), 4.34 (2H, d, J = 8.0 Hz). 5.40 (1H, d, J = 4.8 Hz). 6.01 (2H. D .1 = 54.2 1 Iz). 5.98 (1H.d.1 = 4.8 Hz). 6.0-6.1 (1H.m), 7.03 (IH.d. J = 15.7 Hz) '! (D ₂ O) 3.19 (3H, s). 3.30 (3H. S), 3.32 (3H. S). 3.80 (1H, d, 17.2 Hz), _{| 0} - | , ₇ , ".", ,, 3.86 (II-ld J = 17.2 Hz). 3.98 (211, s). 4..3-4.4 (2H, m). 5.39 (IH.d. 1 () 6; 1760.1660.15) 0 | _{J = 5} , _{Η / χ 5 (2H} . _{() J = 54} , _{2 Hy) 5} . _{98 (1} H. _{T 1} , j = _{5. 1} Hz), 6.0-6.1 i (1 II. 111). 7.04 (1II. Cl, J-15.4 Hz) ——----- 1 --- —__ j

HU 207 088 B

Example number IR spectrum lem ' ¹ Nujol) NMR Spectrum 106 1760. 1650. 1590 (D, O) 3.06 (6H, s), 3.75 (111, d, 3 = 17.2 Hz.). 3.83 (1H, d, 3 = 17.2 Hz), 4.05 (2H, d. 3 = 7.3 Hz). 4.47 (2 H, s). 5.38 (1H, d, J = 4.8 Hz), 5.95 (2H, d, J = 62.2 Hz). 5.95 (1H, d, J = 4.8 Hz), 6.07 UH, dl, J = 7.3 Hz, 15.8 Hz), 7.02 (1H, d, 3 = 15.8 Hz), 7.55 (1H, s), 7.92 (1H, s) 107 (D ₂ O) 3.7-3.9 (6H. Ni). 4.15-4.25 <4H, ni). 4.43 (2H. D. 3 = 7.3 Hz). 5.38 (1H, d, 3 = 4.7 Hz). 5.95 (III. D. 3 = 54.2 1 Iz). 5.97 (1H.d, 3 = 4.7 liters). 6.0-6.1 (1H, ni), 7.06 (111 d. 3 = 15.7 1 Iz) 108 1765. 1670, 1630. 1525 (DMSO-d ₍ ,) 3.27 (2H, brs). 3.42 (1II. D. J = 17.0 Hz) 3.48 (1H, d, 3 = 17.0 Hz) 3.56 (2H. Brs), 3.65 (2H, brs) 3.69 (2H, brs), 5.04 (1H, d, 3 = 4.8 Hz), 5.33 (2H, d, 3 = 7.0 Hz), 5.63 (1H, dd, 3 = 8.4 Hz, 4.8 Hz), 5.78 ( 2H, d, 3 = 55.3 Hz) 5.85-5.95 (1H, m) 7.21 (1H, d, J = 15.8 Hz), 8.20 (2H, d, 3 = 6.6 Hz), 8.22 (2H, s), 9.14 (2H, d, 3 = 6.6 Hz), 9.70 (1H, d, 3 = 8.4 Hz) 109 1760, 1660, 1610. 1575, 1520 (D, O) 3.75 (2H, s). 4.20 (2H, s). 5.01 (211. s). 5.35-5.45 (3H. Ni), 5.96 (2H. D, J = 54.6 Hz). 5.97 (1H, d. 3 = 4.8 Hz). 6.20 (1H. Dt. 3 = 15.8 Hz, 7.5 Hz) .7.03 UH. d. J = 15.8 Hz). 8.14 (2H, d, 3 = 6.2 Hz) .8.88 (2H, d, 3 = 6.2 Hz) 110 1760, 1660, 1615. 1590 _(DMSO-d6) 3:44 (11-1, d, 3 = 16.9 Hz). 3.53 UH. d. 3 = 16.9 Hz), 3.89 (2H, s). 5.07 (1H, d. 3 = 4.8 Hz). 5.12 (brd. 211 3 = 6.0 Hz). 5.68 (1H. Dd. 3 = 4.8 Hz, 8.4 Hz), 5.78 (211. d.3 = 55.7 Hz), 5.92 (1H. Dt, 3 = 15.8 Hz, 6.0 Hz), 7.03 (1H. D, 3 = 15.8 Hz). 7.35 (1 H. brs). 7.85 (2H, d, 3 = 7.0, 10). 8.22 (211, s), 8.60 (2H, d. 3 = 7.0 Hz). 9.73 (1H, d. 3 = 8.4 Hz) 111 (DMSO-d ₍ , -D, O) 2.66 (2H, t. 3 = 7.0 Hz), 3.08 (2H, t. 3 = 7.0 Hz), 3.40 (111.d. 3 = 17.0 Hz) 3.48 UH. d.3 = 17.0 Hz). 5.00 (1H.d. 3 = 5.0 Hz). 5.18 (2H, d. 3 = 7.0 Hz). 5.63 (1H. D .1 = 5.0 Hz). 5.75 (2H, d, J = 55.7 Hz). 5.88 (1H, dd, J = 7.0 Hz, 16.0 Hz). 7.10 (1H. D. 3 = 16.0 Hz), 7.59 (2H. D. 3 = 6.6 Hz). 8.81 (2H, d. 3 = 6.6 Hz) 112 1760. 1655. 1610, 1520 _(DMSO-d6) 2:01 (411, brs). 3.1-3.9 (81-1. M). 4.25-4.4 (2 H, m). 5.10 (1H, d. 3 = 4.8 Hz). 5.7-5.9 (2H. In). 5.79 (2H, d. 3 = 55.0 Hz), 7.04 (1H, d. 3 = 15.7 Hz), 7.39 (1H, brs). 8.22 (2 H, s). 9.74 (1H. D. 3 = 8.5 Hz) 113 1760. 1655, 1575 (DMSO-d 6) 3.41 UH, d, 3 = 16.9 Hz). 3.48 UH, d, J = 16.9 Hz), 3.59 (211 s). 5.04 (1H. D. 3 = 5.1 Hz), 5.28 (211, brs). 5.63 (1H. Brs), 5.78 (211.d, 3 = 55.7 Hz). 5.8-5.95 UH, ni), 7.17 (1H.d.3 = 16.0 Hz), 8.02 UH. dd.3 = 6.2 Hz, 7.7 Hz), 8.22 (2H, s), 8.42 (1H. d.3 = 7.7 Hz), 8.83 (111d, 3 = 6.2 Hz). 8.96 (111s). 9.72 (111th brs) 114 1770, 1690, 1630, 1600 _(DMSO-d6) 3.14 (3H, "s), 15.03 (311 s), 3:48 (IH, d, 3 = 16.8 Hz), 3.66 (1H. D, 3 = 16.8 Hz); 4.03 (1H. D. 3 = 15.5 Hz). 4.06 (1H, d, 3 = 15.5 Hz), 4.17 (2H, brd, 3 = 7.7 Hz), 5.07 (11, d, 3 = 4.8 Hz), 5.65 (1H, dd, 3 = 4.8 Hz) 8.0 Hz), 5.70 (1H, dd, 3 = 7.7 Hz, 15.4 Hz). 7.17 (1H, d, 3 = 15.4 Hz). 7.22 (1 Η, 1.3 = 70.5 Hz), 7.64 (1H, s) 8.29 (3H, s). 9.83 (1H, d. 3 = 8.1) Hz) 115 (D ₂ O) 3.75 (2H, s). 5.39 (1H, d. 3 = 4.7 Hz). 5.44 (2H, d. 3 = 8.0 Hz), 5.97 (1H, d.3 = 4.7 Hz). 6.21 (1II, dl. 3 = 8.0 lzz. 15.0 Hz). 7.07 (111 d. 3 = 15.0 Hz). 7.09 (1H, vol. 3 = 70.0 Hz). 8.37 (2H, d. 3 = 6.7 Hz), 9.01 (2H. D. 3 = 6.7 Hz) 116 1770, 1675.1630.1605 (DMSO-d ₆ > 2.95-3.05 (611. Ni). 3.20-3.30 (6H. Ni). 3.46 (1H. D. 3 = 17.0 l-1z), 3.62 (1H. D. 3 = 17.0 Hz). 3.92 (2H. D. 3 = 7.3 Hz), 5.07 (1H. D. 1 = 5.1 l lz), 5.50-5.70 (211 ni). 7.17 (1I I. d. 3 = 15.8 lz) 7.22 (1H. Vol. 3 = 70.7 Hz). 8.30 (2H. S). 9.83 (III. D. 3 = 7.9 Hz) 117 1770, 1675, 1605 (DM.SO-d ₆ ) 3.40-3.50 (711, ni). 3.70 (1H. D. 3 = 18.2 llz). 3.85 (6H. Brs) .4.10-4.25 (211, m), 5.08 (III.d.3 = 5.0 Hz), 5.66 (1II, dd, 3 = 5.0 Hz, 8.4 Hz), 5.75 (1H, dt, 3 = 7.8 Hz. 15.8 Hz). 7.19 (1H, d, 3 = 15.8 Hz), 7.22 (1 Η, 1.3 = 70.7 Hz), 8.27 (211 s). 9.83 (1H, d, 3 = 8.4 Hz)

HU 207 088 Β

Example E7 p-Methoxybenzyl 7beta- [2- (5-tritylamino-1,2,4-thiadiazol-3-yl) - (Z) -2- (2,2,2-trifluoroethyl) oxy] iminoacetamido (3 - ((Z) -3-chloro-1-propen-1-yl) -cephem-4-carboxylate (starting material of formula 87))

A mixture of 0.247 ml of dimethylformamide and 3 ml of tetrahydrofuran was cooled to -10 ° C and 0.297 ml of phosphorus oxychloride was added and stirred under ice-cooling for 40 minutes. The resulting solution was then treated with 1.36 g of 2- (5-tritylamino-1,2,4-thiadiazol-3-yl) - (Z) -2- (2,2,2-trifluoroethyl) - in 4 ml of tetrahydrofuran. oxyiminoacetic acid was added and stirring was continued at this temperature for 1 hour. The resulting solution was then treated with 1.145 g of p-methoxybenzyl 7-beta-amino-3 - ((Z) 3-chloro-1-propen-1-yl) -3-cephem-4-carboxylate hydrochloride and 2.09 g of N- ( trimethylsilyl) acetamide and 10 ml of ethyl acetate at -20 ° C, and after the addition is complete, the temperature is raised to 0 ° C with stirring over an hour. Ethyl acetate was added to the reaction mixture, washed with water, dried over anhydrous sodium sulfate, the solvent was evaporated, and the residue was chromatographed on silica gel. 1.43 g of the title compound are obtained.

Example 118

7béta- / 2- (5-amino-l, 2,4-thiadiazol-3-yl) - (Z) -2-fluoro-methoxyimino acetamido / 3 - / (E) -3- (carbamoylmethyl dimethylammonio) -1-propen-1-yl / -3-cephem-4-carboxylate (Compound 88)

500 mg of the compound obtained in Example E4 are dissolved in a mixture of 3 ml of methanol and 1 ml of dimethylformamide, 71.3 mg of Ν, Ν-dimethylglycine amide are added under ice-cooling, and the mixture is stirred overnight at room temperature. The reaction mixture was then added to a mixture of ethyl acetate (50 mL) and ethyl ether (50 mL) and the precipitate was collected by filtration to give 382 mg of a yellow powder.

The powder was added to a mixture of trifluoroacetic acid (2.7 mL) and anisole (2.3 mL) and stirred for 1 hour under ice-cooling. The reaction solution was then treated with 25 mL of ethyl ether and 25 mL of isopropyl ether. the precipitate was filtered off with ethyl ether. wash, the precipitate is suspended in 4.5 mL of water and the pH is adjusted to 5.5 to 6.5 with sodium acetate. The insoluble material was collected by filtration and the filtrate was purified by reverse phase chromatography on silica gel to give 94 mg of the title compound.

Example 119

7β- (2- (5-Amino-1,2,4-thiadiazol-3-yl) - (Z) -2-fluoromethoxyiminoacetamido) -3- (E) -3- (1-) methyl 4-sulfamoyl-1-piperazinyl) -1-propen-1-yl / -3-cephem-4-carboxylate (Compound 89)

500 mg of the compound obtained in Example E4 are dissolved in a mixture of 3 ml of methanol and 1 ml of dimethylformamide, 116 mg of N-sulfamoyl-N'-methylpiperazine are added under ice-cooling and the mixture is stirred overnight at room temperature. The reaction mixture was then added to a mixture of ethyl acetate (50 mL) and ethyl ether (50 mL), and the resulting precipitate was collected by filtration and dried to give 402 mg of a yellow powder.

The above powder was stirred in a mixture of trifluoroacetic acid (2.8 mL) and anisole (2.5 mL) for 2 hours under ice-cooling, and then a mixture of ethyl ether (25 mL) and isopropyl ether (25 mL) was added and the precipitate was filtered and washed with ethyl ether. The resulting precipitate was suspended in water (4.5 mL), pH 5.5 and sodium acetate

The insoluble material is filtered off and purified by reverse phase chromatography on silica gel. 58 mg of the title compound are obtained.

Example 120

7β- (2- (5-Amino-1,2,4-thiadiazol-3-yl) - (Z) -2-fluoromethoxyimino-acetamido) -3- (E) -3- ( 1,3,4-Oxadiazol-2-yl) -methyl-dimethylammonio / -1-propenyl-3-cephem-4-carboxylate (Compound 90) Dissolve 500 mg of the compound obtained in Example E4 in 4 ml of methanol. 8 ml of ethyl acetate was added thereto, followed by addition of 88.8 mg of 2-dimethylaminomethyl-1,3,4-oxadiazole in 1 ml of ethyl acetate under ice-cooling, followed by stirring at room temperature overnight. The reaction solution was then added to a mixture of ethyl acetate (50 mL) and ethyl ether (50 mL), the precipitate was filtered off and dried to give 443 mg of a yellow powder.

The above powder was then added under ice-cooling to a mixture of 3.1 ml of trifluoroacetic acid and 2.7 ml of anisole and stirred for 2 hours under ice-cooling. The resulting reaction solution was then added to a mixture of ethyl ether (25 mL) and isopropyl ether (25 mL), and the resulting precipitate was filtered and washed with ethyl ether. The resulting precipitate is then suspended in 4.5 ml of water and the pH is adjusted to 5.5 to 6.5 with sodium acetate. and insoluble matter is filtered off. The filtrate was purified by reverse phase chromatography on silica gel to give 92 mg of the title compound.

Example 121

7β- (2- (5-Amino-1,2,4-thiadiazol-3-yl) - (Z) -2-fluoromethoxyiminoacetamido) -3- (E) -3- (1- methyl 4-carbamoyl-1-piperazinyl) -1-propen-1-yl / -3-cephem-4-carboxylate (Compound 91)

500 mg of the compound obtained in Example E4 are dissolved in a mixture of 3 ml of methanol and 1 ml of dimethylformamide, 100 mg of N-methyl-N'-carbamoylpiperazine are added under ice-cooling and the mixture is stirred overnight at room temperature. A mixture of ethyl acetate (50 mL) and ethyl ether (30 mL) was added to the reaction solution, and the precipitate was collected by filtration and dried to give 425 mg of a yellow powder.

The above powder was then treated with 3 ml of trifluoroacetic acid and

Dissolve in 2.6 ml of anisole mixture and stir for 2 hours under ice-cooling. The reaction solution was then treated with 25 mL of ethyl28

A mixture of ether (208888) and isopropyl ether (25 ml) was added and the precipitate was filtered off and washed with ethyl ether. The precipitate was then suspended in water (4.5 mL), adjusted to pH 5.5 to 6.5 with sodium acetate, and the insoluble material was collected by filtration and the filtrate was purified by reverse phase chromatography on silica gel. 107 mg of the title compound are obtained.

/ 22nd example

7béta- / 2- (5-amino-l, 2,4-thiadiazol-3-yl) - (Z) -2-fluoro-methoxyimino acetamido / 3 - / (E) -3- (l, 2-Dimethylpyrazolidinio) -1-propen-1-yl / -3-cephem-4-carboxylate (A and B isomers) (Compound 92)

783 mg of the compound obtained in Example E4 are dissolved in a mixture of 1.5 ml of methanol and 7.1 ml of ethyl acetate, followed by the addition of 103 mg of Ν, il'-dimethylpyrazolidine in 1.5 ml of ethyl acetate under ice-cooling, and overnight. stirring at room temperature. A mixture of ethyl acetate (50 mL) and ethyl ether (50 mL) was added to the reaction solution, and the resulting precipitate was filtered and dried to give 631 mg of a yellow powder.

The above powder was dissolved in a mixture of 4.5 ml of trifluoroacetic acid and 3.8 ml of anisole and stirred for 2 hours under ice-cooling. The reaction solution was then added to a mixture of 25 ml of ethyl ether and 25 ml of isopropyl ether, and the resulting precipitate was filtered and washed. The precipitate is then suspended in 4.5 ml of water and adjusted to pH 5.5-6.5 with sodium acetate. The insoluble material is separated by filtration and the filtrate is purified by reverse phase chromatography on silica gel to give the desired isomer A (37 mg) and isomer B (27 mg).

Example 123

7béta- / 2- (5-amino-l, 2,4-thiadiazol-3-yl) - (Z) -2-fluoro-methoxyimino acetamido / 3 - / (E) -3- (l- methyl 4-formimidoyl-1-piperazinyl) -1-propen-1-yl / -3-cephem-4-carboxylate hydrochloride (Compound 93) 750 mg of the compound obtained in Example E4 are 4.5 ml of methanol and 1 (5 ml of dimethyl). N-methyl-N'-formimidoylpiperazine hydrochloride (158 mg) was added under ice-cooling and stirred overnight at room temperature. filtered and dried to give 485 mg of a yellow powder.

The above powder was added to a mixture of 3.4 ml of trifluoroacetic acid and 3 ml of anisole, stirred for 2 hours under ice-cooling, and the resulting solution was added to a mixture of 25 ml of ethyl ether and 25 ml of isopropyl ether. The precipitate was filtered off, washed with ethyl ether, suspended in water (4 ml) and the insoluble material was separated by filtration. The filtrate was purified by reverse phase chromatography on silica gel to give 58 mg of the title compound.

A 118-123. The following compounds of Examples 124140 were further prepared as described in Example 1B.

Example 124

7β- (2- (5-Amino-1,2,4-thiadiazol-3-yl) - (Z) -2-fluoromethoxyiminoacetamido) -3- (E) -3- (1-) methyl-1-piperazinio) -1-propen-1-yl / -3-cephem-4-carboxylate (Compound 94)

750 mg of the compound of Example E4 are reacted with 116 μΐ of N-methylpiperazine and deprotected to give 16 mg of the title product.

Example 125

7béta- / 2- (5-amino-l, 2,4-thiadiazol-3-yl) - (Z) -2-fluoro-methoxyimino acetamido / 3 - / (E) -3- (4- carboxypyridinio) -1-propen-1-yl / -3-cephem-4-carboxylate (Compound 95)

750 mg of the compound obtained in Example E4 are reacted with 198 mg of isonicotinic acid and deprotected to give 143 mg of the title compound.

Example 126

7béta- / 2- (5-amino-l, 2,4-thiadiazol-3-yl) - (Z) -2-fluoro-methoxyimino acetamido / 3 - / (E) -3- (l- methylpyrrolidinio) -1-propen-1-yl / -3-cephem-4-carboxylate (Compound 96)

500 mg of the compound of Example E4 are reacted with 55.8 μΐ of N-methylpyrrolidine and deprotected to give 21 mg of the title compound.

/ 27th example

7béta- / 2- (5-amino-l, 2,4-thiadiazol-3-yl) - (Z) -2-fluoro-methoxyimino acetamido / 3 - / (E) -3- (4- carbamoylpyridinio) -1-propen-1-yl / -3-cephem-4-carboxylate (Compound 97)

500 mg of Example E4 is reacted with 131 mg of 4-carbamoylpyridine and deprotected to give 42 mg of the title compound,

Example 128

7béta- / 2- (5-amino-l, 2,4-thiadiazol-3-yl) - (Z) -2-fluoro-methoxyimino acetamido / 3 - / (E) -3- (trimethyl- ammonio) -1-propen-1-yl / -3-cephem-4-carboxylate (Compound 98)

500 mg of the compound of Example E4 are reacted with trimethylamine (neutralized with 57 mg of trimethylamine hydrochloride) and deprotected to give 79 mg of the title compound.

/ 29th example

7β- (2- (5-Amino-1,2,4-thiadiazol-3-yl) - (Z) -2-fluoromethoxyiminoacetamide) -3- (E) -3- (1, 4-Diazabicyclo [2.2.2] octan-1-yl) -1-propen-1-yl / -3-cephem-4-carboxylate (Compound 99)

500 mg of the compound of Example E4 is reacted with 72 mg of 1,4-diazabicyclo [2.2.2] octane and deprotected to give 61 mg of the title compound.

HU 207 088 B

Example 130

7béta- / 2- (5-amino-l, 2,4-thiadiazol-3-yl) - (Z) -2-fluoro-methoxyimino acetamido / 3 - / (E) -3- (l , 5-Diazabicyclo [3.3.0] octan-1-yl) -1-propen-1-yl / -3-cephem-4-carboxylate (Compound 100)

500 mg of Example E4 are reacted with 120 mg of 1,5-diazabicyclo [3.3.0] octane and deprotected to give 32 mg of the title compound.

Example 131

7β- (2- (5-Amino-1,2,4-thiadiazol-3-yl) - (Z) -2-fluoromethoxyiminoacetamido) -3- (E) -3- (4- methylthiomorpholine-1,1-dioxid-4-yl) -1-propen-1-yl / -3-cephem-4-carboxylate (Compound 101)

Example E4 (250 mg) was treated with 4-methylthiomorpholine-1,1-dioxide (52 mg) and deprotected to give the title compound (17 mg).

Example 132

7beta- (2- (5-Amino-1,2,4-thiadiazol-3-yl) - (Z) -2-fluoromethoxyiminoacetamido) -3- (E) -3- (1, 4-Dimethyl-1-piperazinio) -1-propen-1-yl / -3-cephem-4-carboxylate (Compound 102)

500 mg of Example E4 are reacted with 94 μΐ of 1,4-dimethylpiperazine and deprotected to give 35 mg of the title compound.

Example 133

7β- (2- (5-Amino-1,2,4-thiadiazol-3-yl) - (Z) -2-fluoromethoxyiminoacetamido) -3- (E) -3- (2 (aminoethyl) dimethylammonio (-1-propen-1-yl) -3-cephem-4-carboxylate (Compound 103)

750 mg of the compound of Example E4 are reacted with 115 μΙ of N, N-dimethylethylenediamine and deprotected to give 15 mg of the title compound.

Example 134

7β- (2- (5-Amino-1,2,4-thiadiazol-3-yl) - (Z) -2-fluoromethoxyiminoacetamido) -3- (E) -3- (tetrazole) -5-yl) -methyl-dimethylammonio / -1-propen-1-yl-3-cephem-4-carboxylate (Compound 104)

500 mg of the compound obtained in Example E4 is 150 mg

Reaction with 5-dimethylaminomethyl-tetrazole and deprotection gave 37 mg of the title compound.

Example 135

7béta- / 2- (5-amino-l, 2,4-thiadiazol-3-yl) - (Z) -2-fluoro-methoxyimino acetamido / 3 - / (E) -3- (3- sulfopyridinio) -1-propen-1-yl / -3-cephem-4-carboxylate (Compound 105)

750 mg of the compound of Example E4 are reacted with 384 mg of 3-pyridinesulfonic acid and deprotected to give 68 mg of the title compound.

Example 136

7béta- / 2- (5-amino-l, 2,4-thiadiazol-3-yl) - (Z) -2'fluor-methoxyimino acetamido / 3 - / (E) -3 - / (2 -diethylethylaminoethyl) -dimethylammonio / -1-propen-1-yl / -3-cephem-4-carboxylate (Compound 106)

500 mg of the compound of Example E4 is 105 μΐ

Reaction with Ν, Ν, Ν ', Ν'-tetramethylethylene diarinine and deprotection gave 22 mg of the title compound.

Example 137

7beta- (2- (5-Amino-1,2,4-thiadiazol-3-yl) - (Z) -2-fluoromethoxyimino-acetamide) -3- (E) -3- (2-Oxopropyl) dimethylammonio / -1-propen-1-yl / -3-cephem-4-carboxylate (Compound 107)

500 mg of the compound of Example E4 are reacted with 80 μΐ (dimethylamino) acetone and deprotected to give 60 mg of the title product.

Example 138

7beta- (2- (5-Amino-1,2,4-thiadiazol-3-yl) - (Z) -2-fluoromethoxyiminoacetamide; -3- (E) -3- ( 4-Carbamotl-quinuclidinium) -1-propen-1-yl / -3-cephem-4-carboxylate (Compound 108)

500 mg of Example E4 are reacted with 107.6 mg of 4-carbamoylquinuclidine and deprotected to give 77 mg of the title compound.

Example 139

7béta- / 2- (5-Amino-1,2,4-thiadiazol-3-yl) - (Z) -2-fluoro-methoxyimino acetamido / 3 - / (E) -3- / l methyl 2- (2-hydroxyethyl) -pyrrolidin-1-yl-1-propen-1-yl] -3-cephem-4-carboxylate (A and B isomers) (Compound 109)

500 mg of Example E4 are treated with 83.3 mg of 1-methyl-2- (2-hydroxyethyl) -pyrrolidine and deprotected to give the desired A (24 mg) and B (26 mg) isomers.

Example 140

7beta- (2- (5-Amino-1,2,4-thiadiazol-3-yl) - (Z) -2-fluoro-methoxyimino-acetamido) -3- (E) -3- (4 -carboxymethyl 1-pyridinium) -1-propen-1-yl / -3-cephem-4-carboxylate (Compound 110)

Example E4 (500 mg) was treated with 4-pyridylacetic acid hydrochloride (280 mg) and deprotected to give 5 mg of the title compound.

Example 141

7β- (2- (5-Amino-1,2,4-thiadiazol-3-yl) - (Z) -2-fluoromethoxyiminoacetamido) -3- (E) -3- (1, 4,4-Trimethyl-1-piperazinoyl) -1-propen-1-yl] -3-cephem-4-carboxylate iodide (Compound 111). 189 μΐ of 1,4-dimethylpiperazine in ethyl acetate was added dropwise and then stirred overnight. An excellent precipitate is filtered off30

The reaction mixture was separated, re-precipitated in tetrahydrofuran / ethyl acetate and washed with ethyl acetate to give 492 mg of a yellow powder. This material was dissolved in dichloromethane (2 mL), methyl iodide (4 mL) was added under ice-cooling and stirred at this temperature overnight.

The above powder was stirred in a mixture of 1.35 ml of trifluoroacetic acid and 1.16 ml of anisole under ice-cooling for 2 hours, and the resulting solution was added to a mixture of 25 ml of ethyl ether and 25 ml of isopropyl ether. washed with ether, the precipitate is suspended in 4.5 ml of water and the insoluble material is filtered off. The filtrate was purified by reverse phase chromatography on silica gel to give 23 mg of the title compound.

Example 142

7béta- / 2- (5-amino-l, 2,4-thiadiazol-3-yl) - (Z) - (2,2,2-trifluoroethyl) oxyimino-acetamido / 3 - / (E) -3- (Carbamoyl 1-methyl-1-dimethyl-1-ammonium) -1-propen-1-yl] -3-cephem-4-carboxylate (Compound 112)

1.43 g of the product obtained in Example E7 are dissolved in 20 ml of acetone, 0.927 g of sodium iodide is added under ice-cooling, and the mixture is stirred at this temperature for 10 minutes and then stirred at room temperature for 1.5 hours. The solvent was evaporated and ethyl acetate was added to the residue, washed with dilute sodium thiosulfate solution, brine and dried over sodium sulfate. The brine was evaporated and the residue was dissolved in ethyl acetate (40 mL), and dimethylglycine amide (237 mg) was added to the resulting solution and stirred for 1 hour at room temperature. To the resulting solution was then added isopropyl ether and the resulting precipitate was collected by filtration to give 1.07 g of a tan powder.

After stirring for 1 hour under ice-cooling in a mixture of 8 ml of trifluoroacetic acid and 6 ml of anisole, ethyl ether is added to the resulting solution, the precipitate is filtered off, suspended in 10 ml of water and the pH is 5.5-6. Is adjusted to 5 with sodium acetate and the insoluble material is filtered off. The filtrate was purified by reverse phase chromatography on silica gel to give 268 mg of the title compound.

Table 3. Physical data

Example number IR spectrum (cm ^-1 , Nujol) NMR Spectrum (δ) 7 (CDCl ₃ ) 3.22 (1H, d, J = 17.0Hz), 3.50 (1H, d, J = 17.0Hz), 3.55-3.95 (2H, m), 3.74 (3H, s), 4.62 (2H, q, J = 8.3 Hz), 5.01 (1H, d, J = 4.7 Hz), 5.08 (2H, s), 5.66 (1H, dt, J = 11.0 Hz, 7.8 Hz), 5.85 UH, dd, J = 8.5 Hz, 4.7 Hz), 6.18 (1H, d, J = 11.0 Hz), 6.61 (1H, d, J = 8.5 Hz), 6.78 (2H, d, J = 8.5 Hz), 7.0-7.4 (17H, m), 7.48 (1H, brs) 118 1760.1670, 1590 _(DMSO-d6) 3.14 (3H, s), 3.15 (3H, s), 3:47 (IH, d, J = 17Hz), 3.65 (IH, d, J = 17 Hz), 4:02 (2H, s) , 4.16 (2H, d, J = 8Hz), 5.06 (1H, d, J = 5Hz), 5.65 (1H, dd, J = 5Hz, 8Hz), 5.70 (1H, m), 5.80 (2H) , d, J = 55 Hz), 7.16 (1H, d. J = 15 Hz), 7.16 (1H, d. J = 15 Hz), 7.64 (1H, s), 8.19 (1H, s), 8.22 (2H, s), 9.70 (1H, d, J = 8Hz) 119 1765,1670,1600 _(DMSO-d6) 3:01 (3H, s), 3.2-3.6 (9H, m), 3.65 (IH, d, J = 17Hz), 4.12 (2H, d, J = 7Hz), 5:06 (1H, d, J = 5Hz), 5.65 (1H, dd, J = 5Hz, 8Hz), 5.7 (1H, m), 5.78 (2H, d, J = 55Hz), 7.14 (2H, s), 7.21 (1H, d, J = 16Hz), 8.22 (2H, s), 9.70 (1H, d, J = 8Hz) 120 1760, 1665, 1595 _(DMSO-d6) 3:09 (6H, s), 3:48 (IH, d, J = 17Hz), 3.67 (1H, d, J = 17Hz), 4.15 (2H, d, J = 8Hz), 4.97 (2H, s), 5.07 (1H, d, J = 5Hz), 5.65 UH, dd, J = 5Hz, 8Hz), 5.70 (1H, m), 5.78 (2H, d, J = 55Hz) , 7.22 (1H, d, J = 16Hz), 8.22 (2H, s), 9.47 (1H, s), 9.71 (1H, d, J = 8Hz) 121 1765, 1650, 1590 _(DMSO-d6) 3:01 (3H, s), 3.15-3.4 (4H, m), 3.4-3.55 (3H, m), 3.67 (1H, d, J = 18Hz), 3.7-3.8 (2H, m ), 4.11 (2H, m), 5.07 (1H, d, J = 5Hz), 5.66 (1H, dd, J = 5Hz, 8Hz), 5.70 UH, m), 5.78 (2H, d, J = 55 Hz), 6.27 (2H, s), 7.19 (1H, d, J = 16 Hz), 8.20 (2H, s), 9.70 (1H, d, J = 8 Hz)

HU 207 088 B

Example number IR spectrum (cm Nujol) NMR Spectrum (δ) 122-A 1765, 1660, 1595 _(DMSO-d6) 2.15 (2H, m), 2.66 (3H, s), 3.0 (2H, m), 3:02 (2H, m), 3:45 (1H, d, J = I7 Hz), 3:58 (IH, <1.3 = 17 Hz), 3.55-3.75 (2H, m), 4.03 (1H, dd, J = 8 Hz, 13 Hz), 4.19 (1H, dd, J = 8 Hz, 13 Hz), 5.06 ( 1H, d, J = 5Hz), 5.64 (1H, dd, J = 5Hz, 8Hz), 5.65 (1H, m), 5.78 (2H, d, J = 55Hz), 7.19 (1H, d, 1 = 16 Hz), 8.21 (2H, S). 9.70 (1H, d, J = 8Hz) 122-B 1760.1665. 1590 _(DMSO-d6) 2.16 (2H, m), 2.66 (3H, s), 3.0 (2H, m). 3.01 (3H, s), 3.45 (1H, d, J = 17Hz), 3.58 (1H, d, J = 17Hz), 3.6-3.8 (2H, m), 4.01 (1H, dd, J = 7Hz) , 13Hz), 4.21 (1H, dd, J = 7Hz, 13Hz), 5.06 (1H, dd, J = 5Hz, 8Hz), 5.65 (1H, m), 5.78 (2H, d, J = 55Hz), 7.19 (1H, d, 1 = 16Hz), 8.21 (2H, s), 9.69 (1H, d, 1 = 8Hz) 123 1760, 1660, 1590 (DMSO-d _O) 3.12 (3H, s) 3.50 (lH, d, 1 = 18Hz), 3.55 (4H, m), 3.72 (1H, d, J = 18Hz), 3.85-4,15 ( 4H, m), 4.20 (2H, m), 5.11 (1H, d, J = 5Hz), 5.7! (1H, dd, J = 5Hz, 8Hz), 5.79 (2H, d, J = 55Hz), 5.80 (1H, m), 7.19 (1H, d, J = 15Hz), 8.08 (1H, s), 8.22 (2H, s), 9.71 (1H, d. J = 8Hz), 9.70 (1H, br) 124 1765, 1670. 1625 _(DMSO-d6) 3:05 (3H, s), 3.17 (4H, m), 3:35 (4H, m), 3.60 (lH, d, J = 18Hz), 3.95 (1H, d, 1 = 18Hz) , 4.14 (1H, dd, J = 7Hz, 13Hz), 4.21 (1H, dd, J = 7Hz, 13Hz), 5.21 (1H, d, J = 5Hz), 5.79 (2H, d, J = 55 Hz), 5.85 (1H, dd, J = 5 Hz, 8 Hz), 6.12 (1H, m), 7.07 (1H, d, J = 15 Hz). 8.2! (2H, s). 9.78 (1H, d, J = 8Hz) 125 1765, 1660, 1605 _(DMSO-d6) 3:49 (1H, d, J = 17Hz), 3.63 (1H, d, J = 17Hz), 5.12 (1H, d, J = 5Hz), 5.31 (2H, d, J = 7 Hz), 5.74 (1H, dd, J = 5 Hz, 8 Hz), 5.78 (2H, d, J = 55 Hz), 6.07 (1H, dd, J = 8 Hz, 16 Hz), 7.07 (1H, d, J = 16Hz, 7.20 (1H, br), 8.19 (2H, d, J = 7Hz), 8.20 (2H, s), 8.89 (2H, d, J = 7Hz), 9.75 (1H, d, J = 8 Hz) 126 1755, 1650, 1590 _(DMSO-d6) 2:07 (4H, br), 2.95 (3H, s), 3.3-3.4 (4H, m), 3:45 (1H, d. 1 = 17Hz), 3.61 (IH, d, 1 = 17 Hz), 3.99 (2H, d, J = 7Hz), 5.06 (1H, d, J = 5Hz), 5.63 (1H, dd, J = 5Hz, 8Hz), 5.7 (1H, m), 5.78 (2H, d, J = 55 Hz). 7.18 (1H, d, J = 16Hz), 8.22 (2H, s), 9.69 (1H, d, J = 8Hz) 127 1760,1665,1595 _(DMSO-d6) 3:41 (IH, d, 1 = 2.17 Hz), 3:48 (IH, d, 1 = 2.17 Hz), 5:04 (IH, d, 1 = 4.8 Hz), 5:35 (2H, d, 1 = 7.0 Hz), 5.64 (1H, dd, J = 4.8 Hz, 8.5 Hz), 5.78 (2H, d, J = 55.3 Hz), 5.88 (1H, dd, J = 15.8 Hz, 7.0 Hz), 7.25 (1H, d, J = 15.8 Hz, 8.22 (2H, s), 8.24 (1H, s), 8.43 (2H, d, J = 6.8 Hz), 8.79 (1H, s), 9.19 (2H, d, 1) = 6.8 Hz), 9.71 (1H, d, J = 8.5 Hz) 128 1765.1595 _(DMSO-d6) 2.99 (9H, s), 3:46 (1H, d, 1 = 17.0 Hz). 3.63 (1H, d, J = 17.0 Hz), 3.98 (2H, d, J = 7.3 Hz), 5.05 (1H, d, J = 5.0 Hz). 5.60-5.70 (2H, m), 5.78 (2H, d, J = 55.3 Hz), 7.18 (1H, d, J = 15.8 Hz), 8.25 (2H, s). 9.84 (1H, d, J = 8.4 Hz) 129 1760, 1595 _(DMSO-d6) 2.90-3.10 (6H, m), 3:15 to 3:35 (6H, m), 3:46 (IH, d, 1 = 9.16 Hz), 3.60 (IH, d, J = 16.9 Hz), 3.92 ( 2H, d, J = 7.3 Hz). 5.05 (1H, d, J = 5.1 Hz), 5.50-5.70 (2H, m), 5.79 (2H, d, J = 55.3 Hz), 7.17 (1H, d, 1 = 15.8 Hz), 8.25 (2H, s) ), 9.70 (1H, d, J = 8.0 Hz)

HU 207 088 Β

Example number IR spectrum (cm ^-1 , Nujol) NMR Spectrum (δ) 130 1760, 1595 _(DMSO-d6) 2:15 to 2:37 (4H, m), 3:00 to 3:15 (2H, m), 3:20 to 3:35 (2H, m), 3:44 (IH, d, J = 9.16 Hz), 3:54 UH, d, J = 16.9 Hz), 3.54 (1H, d, J = 16.9 Hz). 3.60-3.82 (4H, m), 4.08 (2H, d, J = 6.6 Hz), 5.05 (1H, d, J = 5.1 Hz),? 5.60-5.70 (2H, m), 5.79 (2H, d, J = 55.3 Hz). 7.19 UH, d. J = 15.8 Hz). 8.24 j (2H, s), 9.70 (1H, d, J = 8.5 Hz) 131 1765,1670,1600 _(DMSO-d6) 3.16 (3H, s), 3:47 (1H, d, J = 17Hz), 3.65-3.75 (5H, m), 3.80-3.90 (4H, m), 4.27 (1H, dd, J = 7 Hz, 13 Hz), 4.33 (1H, dd, J = 7 Hz, 13 Hz), 5.09 (1H, d, J = 5 Hz), 5.67 (1H, dd, J = 5 Hz, 8 Hz), 5.7-5.8 (1H, m), 5.79 (2H, d, J = 55Hz), 7.26 (1H, d, J = 15Hz), 8.21 (2H, s), 9.71 (1H, d, J = 8Hz) ) 132 1765.1670, 1595 _(DMSO-d6) 2.27 (3H, s), 2.60 (2H, m), 2.75 (2H, m), 2.97 (3H, s), 3.3 (4H, m), 3:45 (lH, d, J = 17 Hz), 3.63 (1H, d, J = 17Hz), 4.07 (2H, d, J = 8Hz), 5.05 (1H, d, J = 5Hz), 5.64 (1H, dd, J = 5Hz, 8Hz), 5.69 (1H, m), 5.78 (2H, d, J = 55Hz), 7.20 (1H, d, J = 16Hz), 8.22 (2H, s), 9.70 (1H, d, J = 8Hz) 133 1765.1670, 1600 (DMSO-d _O) 3.27 (6H, s), 3.65 (2H, m), 3.72 (2H, m), 3.78 (IH, d, J = 17Hz), 3.84 (IH, d, J = 17Hz) , 4.22 (2H, d, J = 8Hz), 5.40 (1H, d, J = 5Hz), 5.97 (2H, d, J = 55Hz), 5.98 (1H, d, J = 5Hz), 6.09 (1H, dt, J = 8Hz, 16Hz), 7.07 (1H, d, J = 16Hz) 134 1760.1665. 1595 _(DMSO-d6) 2.89 (3H, s), 2.90 (3H, s) 3.50 (1H, d, J = 17Hz), 3.67 (IH, d, J = 7Hz), 3.96 (1H, d , J = 7Hz), 4.61 (2H, s), 5.08 (1H, d, J = 5Hz), 5.66 (1H, dd, J = 5Hz, 8Hz), 5.79 (2H, d, J = 56 Hz), 5.82 (1H, dt, J = 7Hz, 15Hz), 7.20 (1H, d, J = 15Hz), 8.21 (2H, s), 9.72 (1H, d, J = 8Hz) 135 1765,1670,1620, 1590, 1530, 1240, 1215 _(DMSO-d6) 3:46 (IH, d, J = 17.2 Hz) 3.55 (1H, d, J = 2.17 Hz), 5:09 (IH, d, J = 4.8 Hz), 5:39 (2H, brs) , 5.70 (1H, brs), 5.78 (2H, d, J = 55.3 Hz), 5.98 (1H, dt, J = 15.8 Hz, 6.5 Hz), 7.20 (1H, d, J = 15.8 Hz), 8.13 (1H , dd, J = 8.0 Hz, 6.0 Hz), 8.20 (2H, s), 8.69 (1H, d, J = 8.0 Hz), 8.98 (1H, d, J = 6.0 Hz), 9.24 (1H, s), 9.73 (1H, d, J = 8.5 Hz) 136 1765.1670, 1600 _(DMSO-d6) 2.26 (6H, s), 2.74 (2H, m), 3:04 (6H, s), 3:42 (2H, m), 3.62 (IH, d, J = 18Hz), 3.98 (1H, d. J = 18 Hz), 4.11 (2H, d, J = 8 Hz), 5.23 (1H, d, J = 5 Hz), 5.79 (2H, d, J = 55 Hz), 5.86 (1H, m) , 6.13 (1H, dt, J = 8Hz, 15Hz), 7.02 (1H, d, J = 15Hz), 8.21 (2H, s), 9.79 (1H, d, J = 8Hz) 137 1760, 1665, 1595 _(DMSO-d6) 2.17 (3H, s) 3.09 (3H, s), 3.10 {3H, s), 3:45 (IH, d, J = 17Hz), 3.63 (1H, d, J = 17Hz) , 4.10 (2H, d, J = 8Hz). 4.48 (2H, s), 5.06 (1H, d, J = 5Hz), 5.64 (1H, dd, J = 5Hz, 8Hz), 5.68 (1H, dt, J = 8Hz, 16Hz), 5.79 (2H, d, J = 55Hz), 7.12 (1H, d, J = 16Hz), 8.22 (2H, s), 9.70 (1H, d, J = 8Hz) 138 1760, 1655, 1590 _(DMSO-d6) 3:25 to 3:45 (12H, m), 3:45 (IH, d, J = 17Hz), 3.61 (1H, d, J = 17Hz), 3.88 (2H, d, J = 7Hz) , 5.06 UH, d. J = 5Hz, 5.62 (1H, m), 5.63 (1H, dd, J = 5Hz, 8Hz), 5.78 (2H, d, J = 55Hz), 7.11 (1H, s), 7.15 (1H) , d, J = 16Hz), 7.34 (1H, s), 8.23 (2H, s), 9.70 (1H, d, J = 8Hz) 139-A 1760,1650,1590 (DMSO-d _h) 1,6-2.4 (6H, m) 3.00 (3H, s), 3.2-3.7 (5H, m), 3:44 (1H, d, J = 17Hz), 3.66 (IH, d , J = 17 Hz), 3.69 (2H, d, J = 8 Hz), 5.06 UH, d, J = 5 Hz), 5.64 UH, dd, J = 5 Hz, 8 Hz), 5.67 (1H, m) , 5.78 (2H, d, J = 55 Hz), 7.18 (1H, d, J = 15 Hz), 8.24 (2H, s), 9.69 (1H, d, J = 8 Hz)

HU 207 088 B

Example number IR spectrum (cm ^-1, Nujol) i NMR Spectrum (δ) ' 139-B 1760, 1650, 1590 _(DMSO-d6) 1.6-2.4 (6H, m) 3.00 (3H, s), 3.2-3.7 (5H, m), 3:46 (IH, d, '3 = 17Hz), 3.63 (IH, d, 3 = 17Hz), 3.75 (2H, d, 3 = 7Hz), 5.06 (1H, d, 3 = 5Hz), 5.64 (1H, dd, 3 = 5Hz, 8Hz), 5.67 (1H, m), 5.79 (2H, d, 3 = 55 Hz); 7.16 (1H, d, J = 16Hz), 8.21 (2H, s), 9.70 (1H, d, 3 = 8Hz)! 140 (DMSO-d _fl), 5:02 (1H, d, J = 4.8 Hz). 5.22 (2H, d, 3 = 6.6 Hz), 5.61 (1H, dd, J = 4.8 Hz, 8.4 Hz), 5.77 (2H, d, 3 = 55 Hz), 5.8-5.9 (1H.m), 7.31 (1H, d. 3 = 15.0 Hz), 7.97 (2H, d, 3 = 6.2 Hz), 8.20 (2H, s), 8.86 (2H, d, 3 = 6.2 Hz), 9.70 (1H, d, 3 = 8.4 Hz) 141 1760, 1670. 1595 _(DMSO-d6) 3:09 (6H, s), 3.18 (3H, s), 3:51 (1H, d, 3 = 17Hz), 3.74 (IH, d, 3 = 17Hz), 3.83 (8H, br ), 4.34 (2H, m), 5.12 (1H, d, 3 = 5Hz), 5.73 (1H, m) ,; 5.78 (2H, d, 3 = 55Hz), 5.83 (1H, m), 7.24 (1H, d, 3 = 15Hz), 8.21 (2H, s),: 9.92 (1H, d, 3 = 8Hz) 142 1762, 1680, 1590 _(DMSO-d6) 3.10 (6H, s), 3.3-3.7 (2H, m). 3.9-4.3 (4H, m), 4.71 (2H, q,: 3 = 9.0 Hz), 4.98 (1H.d, 3 = 5.0 Hz), 5.4-5.8 (2H, m), 7.13 (1H.d, 3 = 15.5 ^! Hz). 7.55 (1H, brs), 8.17 (2H, brs), 8.40 (1H, brs), 9.57 (1H, d 3 = 8.0 Hz)

Example 143

7béta- / 2- (5-amino-l, 2,4-thiadiazol-3-yl) - (Z) -2-fluoro-pyridylmethoxyimino acetamido / 3 - / (E) -3- / tris ( 2-Hydroxyethylammonio / -1-propen-1-yl / -3-cephem-4-carboxylate (Compound 113)

400 mg of the compound obtained in Example E4 are dissolved in 4 ml of ethyl acetate, 96 mg of triethanolamine in 4 ml of ethyl acetate are added, the solution is stirred for 6 hours at room temperature, 24 ml of diisopropyl ether are added and the precipitate is filtered off . The precipitate was then added to 4.5 ml of a 1: 1 mixture of trifluoroacetic acid and anisole under ice-cooling and stirred for 1.5 hours at room temperature. To the resulting solution was added 18 ml of diisopropyl ether, the precipitate was filtered off and washed with diisopropyl ether.

The precipitate was then suspended in water (3 mL) and adjusted to pH 6 with sodium acetate. The insoluble material was separated by filtration and the filtrate was purified by reverse phase chromatography on silica gel to give 17 mg of the title compound.

Example 144

7beta- (2- (5-Amino-1,2,4-thiadiazol-3-yl) - (Z) -2-fluoromethoxyiminoacetamido) -3- (E) -3- bis - (2-hydroxyethyl) methylammonio / -1-propan-1-yl / -3-cephem-4-carboxylate (Compound 114)

In the same manner as in Example 143, 500 mg of the compound of Example E4 are reacted with 150 mg of N-methyl diethanolamine and deprotected to give 15 mg of the title compound.

Example number IR spectra (cm ^first Nujol) í Nuclear Magnetic Resonance Spectrum (8) 143 _(DMSO-d6) 3:43 (6H, brs), 3:47 (1H. D. = 3 17Hz), 3.69 (1H. D, i 3 = 17 Hz), 3.84 (6H, brs). 4.16 (2H, d, 3 = 7Hz), 5.07 (1H, d, 3 = 5Hz), 5.67: (1H, dd, 3 = 8Hz, 5Hz), 5.7-5.8 (1H, m), 5.78 (2H, brd, 3 = 56 Hz) ,; 7.15 (1H, d, 3 = 16 Hz), 8.21 (2H, s), 9.70 (1H, d, 3 = 8 Hz): 144 1760, 1670. 1600 (D ₂ O) 3.23 (3H, s), 3.60-3.70 (4H, m), 3.77 (1H, d, 3 = 17.6 Hz), 3.83 | UH, d, 3 = 17.6 Hz), 4.1-4.2 (4H, m), 4.27 (2H, d, 3 = 7.4 Hz), 5.39 (1H, d, 3 = 4.8 Hz), 5.96 (2H, d, 3 = 54.6 Hz), 5.98 (1H, d, 3 = 4.8 Hz), 6.0-6.1 (1H, m), 7.03 (1H.d, 3 = 15.7 Hz). I 11

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Example E8

2- (5-Tritylamino-1,2,4-thiadiazol-3-yl) - (Z) -2-cyanomethoxyimino-acetic acid (starting material of formula 115) g N-cyanomethoxyphthalimide 50 g slurried in ethanol (1.93 ml), hydrazine monohydride (1.93 ml) was added at room temperature and the resulting mixture was stirred for 1 hour and 45 minutes. Saturated brine and ethyl ether were added, the mixture was made basic with concentrated aqueous ammonia and extracted with ethyl ether. The ethyl ether extract was washed with brine, dried over anhydrous sodium sulfate, and the solvent was distilled off. To the residue was added 650 g of 2- (5-tritylaminol, 2,4-thiadiazol-3-yl) glyoxylic acid in 350 ml of methanol and the resulting mixture was stirred at room temperature for 1 hour. The solvent was distilled off and the residue was dissolved in ethyl acetate, washed with 0.1 N hydrochloric acid and brine. The organic layer was dried over anhydrous sodium sulfate and the solvent was distilled off to obtain 7.64 g of the title compound.

Example E9 p-Methoxybenzyl 7beta- [2- (5-trityl-1-amino-1,2,4-thiadiazoth-3-yl) - (Z) -2-cyanomethoxyimino-acetamido] -3 - ((Z) -3-chloro-1-propen-1-yl) -3-cephem-4-carboxylate (starting material of formula 116)

A mixture of dimethylformamide (1.51 ml) and tetrahydrofuran (18 ml) was cooled to -10 ° C, phosphoryl chloride (1.82 ml) was added, and the resulting mixture was stirred under ice-cooling for 40 minutes, then 7.64 g of E8 dissolved in 24 ml of tetrahydrofuran were added. and the resulting mixture was stirred at this temperature for an additional hour.

g of p-methoxybenzyl 7-beta-amino-3 - ((Z) -3-chloro-propen-1-yl) -3-cephem-4-carboxylate hydrochloride, 12.8 g of N-trimethylsilylacetamide and A solution of ethyl acetate (ml) was cooled to -25 ° C, the reaction mixture was added and stirred at 0 ° C for 40 minutes. The reaction mixture was extracted with ethyl acetate, and the organic layer was washed with brine and then dried over anhydrous sodium sulfate. The solvent was distilled off and the residue was chromatographed on silica gel to give 7.8 g of the title compound.

Example E10 p-Methoxybenzyl 7beta- (2- (5-tritylamino-1,2,4-thiadiazol-3-yl) - (Z) -2-cyanomethoxyiminoacetamido] -3- (E). ) -3-iodo-1-propen-1-yl / -3-cephem-4-carboxylate (starting material of formula 117)

7.8 g of Example E9 are dissolved in 120 ml of acetone, 6.9 g of sodium iodide are added under ice-cooling, and the mixture is stirred for 10 minutes at this temperature and then for 1.5 hours at room temperature. The solution was then distilled off, the residue was extracted with ethyl acetate, and the extract was washed with dilute aqueous sodium thiosulfate solution and brine and dried over anhydrous sodium sulfate. The solution was then concentrated and added dropwise to a mixture of isopropyl ether and ethyl ether. The precipitate was collected by filtration to give 6.5 g of the title compound.

Example 145

7béta- / 2- (5-amino-l, 2,4-thiadiazol-3-yl) - (Z) -2-cyano-methoxyimino acetamido / 3 - / (E) -3 - / (S -carbamoyl-2-hydroxyethyl) -dimethylammonio-1-propenyl-3-cephem-4-carboxylate (Compound 118) g of Example E10 was dissolved in 2 ml of dimethylformamide, and 210 mg of (1S-Carbamoyl-2-hydroxyethyl) -dimethylamine is stirred at room temperature for 1.5 hours and finally 10 ml of ethyl acetate are added. The resulting solution was then added dropwise to 100 ml of ethyl ether to give 710 mg of a brown precipitate.

The resulting precipitate was added to a mixture of 6 ml of anisole and 6.5 ml of trifluoroacetic acid and stirred for 1 hour under ice-cooling. Ethyl ether was added to give a brown precipitate (430 mg). It is suspended in 10 ml of water, adjusted to pH 7 with sodium acetate, filtered and the filtrate is purified by reverse phase chromatography on silica gel to give 50 mg of the title compound.

Example 146

7béta- / 2- (5-amino-l, 2,4-thiadiazol-3-yl) - (Z) -2-cyano-methoxyimino acetamido / 3 - / (E) -3- (l- methyl 2R-hydroxymethyl-4R-hydroxy-1-pyrrolidinio) -1-propenyl-3-cephem-4-carboxylate (Compound 119) g of Example E10 in 10 mL of ethyl acetate and 8 mL of ethyl acetate. After stirring overnight, 167 mg of N-methyl-4R-hydroxy-D-proline were added, 100 ml of ethyl ether were added and the precipitate was collected by filtration. This is 840 mg of a yellow powder.

To the above powder was added dropwise a mixture of 6 ml of anisole and 8 ml of trifluoroacetic acid under ice-cooling for 30 minutes, followed by stirring for 1.5 hours, and finally 100 ml of ethyl ether. The precipitate was filtered off, suspended in 4 ml of water and adjusted to pH 7 with sodium acetate. The insoluble material was then filtered off and the filtrate was purified by reverse phase chromatography on silica gel to give 24 mg of the title compound.

The following pages 147-154. In Examples 1 to 4, the compounds of Formula 120 of Example E10 and Compound A, A 'of Formula 121 can be prepared by following the procedure described in Examples 145 to 146 above.

In cases where multiple isomers are formed, the yield refers to the isolated isomer.

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Example number THE The amount of starting compound A '(amine) IU. Example Yield: 147 / OH ^ OH 960 mg 3.0 g 37 mg 148 ^ Π '/ CH, —'N — Α «· η CH, ^Vo11 500 mg 1.0 g 50 mg 149 CH, -ν ^ Ύ ⁰¹¹ CH, CH, 0.19 ml (racemate) 1.0 g 113 mg (1: 1 mixture) 150 CH, QJT -Μ ™ --ψΙ1 '* ·' 1 CH, '- CONHj 250 mg ^H A ch, z ^N X H, C CONH, (racemate) 1.0 g 43 mg 151 122 24 mg 152 _ * OH γΟ CH, OH 120 mg 800 mg 120 mg 153 CH, θ ^Π 'Uh CH, ^X CONH, 470 mg 2.0 g 31 mg 154 CH, -'Í '-' V CH, ⁰ 0.32 mL 2.0 g 120 mg

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Example number IR spectrum (cm ^-1 , Nujol) NMR Spectrum (δ) 8 (CDCl 3) 4.86 (2H, s), 7.29 (15H, s), 8.10 (1H, brs) 9 (CDCl 3) 3.25-3.6 (2H, m), 3.6-4.1 (2H, m), 3.75 (3H, s), 4.90 (2H, s), 5.02 (1H, d, J = 5.0 Hz), 5.08 (2H, s), 5.66 (1H, dt, J = 11.3 Hz, 7.7 Hz), 5.82 (1H, dd. J = 9.0 Hz, Hz), 6.18 (1H, d, J = 11.3 Hz), 6.79 (2H, d, J = 8.6 Hz), 6.95 (1H, d .1 = 9.0 Hz). 7.0-7.35 (17H, brs), 7.59 (1H, brs) 10 1770, 1715, 1675, 1605 (CDCl ₃ ) 3.35-3.65 (2H, m), 3.74 (3H, s), 3.8-4.10 (2H, m), 4.86 (2H, s), 4.95 (1H, d, J = 5.0 Hz), 5.13 ( 2H, s), 5.7-6.35 (3Η, m), 6.5-7.4 (20H, m), 7.66 (1H, brs) 145 1770, 1685, 1600, 1530 _(DMSO-d6) 3:08 (3H, s), 3.15 (3H, s), 3:48 (IH, d, J = 17.0 Hz), 3.67 (IH, d, J = 17.0 Hz), 3.87 (IH, dd, J = 8.1 Hz, 14.3 Hz), 4.05-4.15 (2H, m), 4.154.25 (2H, m), 5.07 (1H, d, J = 4.8 Hz), 5.10 (2H, s). 5.66 (1H, dd, J = 4.8 Hz, 8.1 Hz), 5.75-5.85 (1H, m). 7.14 (1H, d, J = 15.8 Hz). 7.75 (1H, s), 8.24 (2H, s), 8.38 (1H, s), 9.73 (1H, d, J = 8.1 Hz) 146 1765, 1660, 1595, 1530 _(DMSO-d6) 1.78 (IH, m), 2:55 (IH, tn), 3:04 (3H, s), 3:47 (IH.d, J = 16.9 Hz), 3.6-4.0 (5H. M), 3.66 ( 1H, d, J = 16.9Hz, 4.18 (2H, m), 4.45 (1H, brs), 5.05 (1H, d, J = 5.1Hz), 5.10 (2H, s), 5.6-5.8 (1H, m) ), 5.63 (1H, dd, J = 5.1 Hz, 8.1 Hz), 7.13 and 7.17 (total 1H, d, J = 15.9 Hz), 8.24 (2H, s), 9.71 (1H, d, J = 8.1 Hz) 147 1765, 1670, 1600 _(DMSO-d6) 3:40 to 3:50 (7H, .m), 3.67 (lH, d, J = 17.2 Hz), 3.85 (6H, brs), 4:10 to 4:25 (2H, m), 5:06 (1H, d, J = 5.0 Hz), 5.10 (1H, s), 5.65 (1H, dd, J = 5.0 Hz, 8.3 Hz), 5.75 (1H, dt, J = 7.0 Hz, 15.8 Hz), 7.14 (1H, d, J) = 15.8 Hz), 8.24 (2H, s). 9.71 (1H, d, J = 8.3 Hz) 148 1760, 1660, 1590, 1520 _(DMSO-d6) 1:32 (3H, d, J = 6.6 Hz), 2.94 (3H, s), 2.98 (3H, s), 3:40 to 3:50 (IH, m), 3:47 (lH, d, J = 16.9 Hz), 3.65 (1H, d, J = 16.9 Hz), 3.65-3.75 (1H, tn), 3.80-3.90 (1H, ni), 4.04 (2H, brd, 1 = 1.1 Hz), 5.05 (1H, d) , J = 4.8Hz), 5.10 (2H, s), 5.63 (1H, dd, J = 4.8Hz, 8.4Hz), 5.65-5.75 (1H, m), 7.18 (1H, d, J = 15.8Hz), 8.26 (2H, s), 9.71 (1H, d, J = 8.4 Hz) 149 1765,1670,1600,1530 _(DMSO-d6) 1.11 (3H, d, J = 6.2 Hz), 3:01 (3H, s), 3:04 (3H, s), 3.22 (2H, brs), 3:47 (1H, d, J = 7.2 Hz ), 3.63 and 3.66 (total 1H, d, J = 17.2 Hz), 4.05 (2H, brs), 4.26 (1H, brs), 5.05 (1H, d, J = 4.8 Hz), 5.10 (2H, s), 5.63 (1H, dd, J = 4.8 Hz, 8.4 Hz), 5.65-5.75 (1H, m), 7.16 (1H, d, J = 15.4 Hz), 8.27 (2H, s), 9.71 (1H.d, J) = 8.4 Hz) 150 1765, 1675, 1595, 1530 _(DMSO-d6) 1:47 (3H, d, J = 6.6 Hz), 3:06 (3H, s), 3:08 (3H, s), 3:49 (IH, d, J = 17.0 Hz), 3.64 (1H, d, J = 17.0 Hz), 4.0-4.2 (3H, m), 5.06 (1H, d, J = 4.8 Hz), 5.10 (2H, s), 5.65 (1H, dd, J = 4.8 Hz, 8.4 Hz), 5.65 -5.80 (1H, m), 7.16 (1H, d, J = 15.8 Hz), 7.68 (1H, s), 8.25 (2H, s), 8.41 (1H, s), 9.73 (1H, d, J = 8.4) Hz) 151 1765, 1680, 1595, 1530 _(DMSO-d6) 1:45 (3H, d, J = 6.6 Hz), 3:02 (3H, s), 3:07 (3H, s), 3:51 (1H, d, J = 16.9 Hz), 3.65 (IH, d, J = 16.9 Hz, 4.0-4.1 (1H, m), 4.35-4.45 (2H, m), 5.08 (1H, d, J = 4.8 Hz), 5.10 (2H, s), 5.66 (1H, dd, J) = 4.8 Hz, 8.1 Hz), 5.70-5.85 (1H, tn), 7.26 (1H, d, J = 15.4Hz), 7.64 (1H, s), 8.24 (2H, s), 8.95 (1H, s), 9.72 (1H, d, J = 8.1 Hz) 152 1765, 1660, 1630, 1600, 1590, 1540 _(DMSO-d6) 1.95-2.10 (IH, tn), 2:15 to 2:40 (IH, tn), 2.93 (2H, s), 3.14 (IH, s), 3.40-3.65 (3H, s). 3.48 (1H, d, J = 16.9 Hz), 3.64 (1H, d, J = 16.9 Hz), 3.65-3.90 (2H, tn), 3.95-4.10 (1H, m), 4.10-4.25 (1H, m). , 4.40 (1H, brs), 5.06 (1H, d, J = 4.8 Hz), 5.10 (2H, s), 5.64 (1H, dd, J = 4.8 Hz, 8.4Hz), 5.70-5.85 (1H, m) , 7.13 and 7.16 (total 1H, d, J = 15.4Hz), 8.24 (2H, s), 9.72 (1H, d, J = 8.4Hz)

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Pclda number IR spectrum (cm ^-1 , Nujol) NMR Spectrum (5) 153 1760. 1665, 1590. 1520 _(DMSO-d6) 1.20 (3H, d, J = 6.2 Hz), 3:06 (3H, $), 3.22 (3H, s), 3:49 (IH, d. J = 17.2 Hz), 3.62 (IH, d, J-17.2 Hz), 3.96 (1H, d, J = 9.2 Hz), 4.15-4.45 (3H, s), 5.07 (1H, d, J = 5.2 Hz), 5.10 (2H, s). 5.66 (1H, dd. J = 5.2 Hz, 8.4 Hz). 5.8-5.9 (1H, m), 7.02 (1H, d, J = 15.8 Hz). 7.83 (1H, s), 8.24 (2H, s). 8.71 (1H, s), 9.72 (1H, d, J = 8.4 Hz) 154 1760, 1660, 1590, 1520 _(DMSO-d6) 2.16 (3H, s) 3.09 (3H, s), 3.10 (3H, s), 3:46 (IH, d, J = 17.0 Hz), 3.63 (1H, d, J = 17.0 Hz) , 4.12 (2H. D. J = 7.3 Hz). 4.51 (2 H, s). 5.05 (1H, d, J = 5.1Hz), 5.10 (2H, s), 5.63 (1H, dd, J = 5.1Hz, 8.1Hz), 5.65-5.75 (1H, m), 7.13 (1H, d, J) = 15.4 Hz), 8.26 (2H, s), 9.71 (1H, d, J = 8.1 Hz)

Example 155

7β- (2- (5-Amino-1,2,4-thiadiazol-3-yl) - (Z) -2-cyanomethoxyiminoacetamido) -3- (E) -3- carbamoylmethyldimethylammonio) -1-propen-1-yl--3-cephem-4-carboxylate (Compound 123) mg of dimethylglycine amide was added to 390 mg of Example E10 obtained in 15 ml of ethyl acetate at room temperature. After stirring for 1 hour, ethyl ether was added and the resulting precipitate was filtered. After drying, 260 mg of a brown powder are obtained.

To the above powder was added a mixture of 2 ml of trifluoroacetic acid and 1.5 ml of anisole, stirred for 1 hour under ice-cooling, ethyl ether was added to the resulting solution, the resulting precipitate was filtered off and washed with ethyl acetate. The precipitate is then suspended in 5 ml of water, adjusted to pH 5.5 to 6.5, and the insoluble material is filtered off. The filtrate was purified by reverse phase chromatography to give 37 mg of the title compound.

Example 156

7β- (2- (5-Amino-1,2,4-thiadiazol-3-yl) - (Z) -2-cyano-40-methoxyiminoacetamide) -3- (E) -3 - (1-Methylsulfamoyl-1-piperazinyl) -1-propen-1-yl / -3-cephem-4-carboxylate (Compound 124)

Dissolve 500 mg of the compound prepared in Example E10 in a mixture of dichloromethane (1 ml) and methanol (1 ml), add N-sulfamoyl-N'-methylpiperazine (145 mg), stir at room temperature for 4 hours and concentrate the solution with ethyl ether. The precipitate was filtered off and dried to give 450 mg of a tan powder.

The above powder was added to a mixture of 3.5 ml of trifluoroacetic acid and 3 ml of anisole, stirred for 1 hour, then ethyl ether was added to the resulting solution and the precipitate was filtered off and dried over ethyl ether. washed. The precipitate is then suspended in 5 ml of water, adjusted to pH 5.5 to 6.5, and the insoluble material is filtered off. The filtrate was purified by reverse phase chromatography to give 39 mg of the title compound. 60

Example 157

7beta- (2- (5-Amino-1,2,4-thiadiazol-3-yl) - (Z) -2-cyanomethoxyiminoacetamido) -3- (E) -3- (1, 4-Diazabicyclo [2,2,2] octan-1-thio) -1-propen-1-yl] -3-cephem-4-carboxylate (Compound 125)

500 mg of the compound obtained in Example E10 are dissolved in a mixture of 6 ml of ethyl acetate and 0.5 ml of methanol, 90 mg of 1,4-diazabicyclo [2.2.2] octane are added and the resulting mixture is stirred at room temperature for 20 minutes. Ethyl ether was added to the solution and the precipitate was filtered off and dried to give 330 mg of a tan powder.

The above powder was mixed with 3 ml of trifluoroacetic acid and 2.5 ml of anisole, stirred for 1 hour under ice-cooling, then added with ethylene and the precipitate was washed with ethyl ether. The precipitate is then suspended in 5 ml of water, adjusted to pH 5.5 to 6.5, and the insoluble material is filtered off. The filtrate was then purified by reverse phase chromatography to give 48 mg of the title compound.

The following paragraphs 158-161. Examples 155-157. were prepared according to examples.

Example 158

7béta- / 2- (5-Amino-1,2,4-thiadiazol-3-yl) - (Z) -2-cyano-was allowed to react-acetamido / 3 - / (E) -3- (4- carbamoyl-1-pyridinyl) -1-propen-1-yl / -3-cephem-4-carboxylate (Compound 126)

600 mg of the compound of Example E10 are reacted with 235 mg of 4-carbamoylpyridine and deprotected. 37 mg of the title compound are obtained.

Example 159

7béta- / 2- (5-Amino-1,2,4-thiadiazol-3-yl) - (Z) -2-cyano-methoxyimino acetamido / 3 - / (E) -3- (S 3,4-Oxadiazol-2-yl) -methyl-dimethylammonio / -1-propen-1-yl / 3-cephem-4-carboxylate (Compound 127)

600 mg of the compound of Example E10 are reacted with 163 mg of 2-dimethylaminomethyl-1,3,4-oxadiazole and deprotected to give 54 mg of the title compound.

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Example 160

7β- (2- (5-Amino-1,2,4-thiadiazol-3-yl) - (Z) -2-cyanomethoxyiminoacetamido) -3- (E) -3- (1, 2-Dimethyl-1-piperazinyl) -1-propan-1-yl] -3-cephem-4-carboxylate (A and B) (Compound 128) 510 mg of the compound obtained in Example E10 in 0.4 ml.

Reaction with 1,2-dimethylpyrazolidine followed by deprotection. The desired isomer A (20 mg) and B (20 mg) are obtained.

Example 161

7béta- / 2- (5-amino-l, 2,4-thiadiazol-3-yl) - (Z) -2-cyano-methoxyimino acetamido / 3 - / (E) -3- (l, 5-Diazabicyclo [3.3.1] octan-1-thio) -1-propen-1-yl] -3-cephem-4-carboxylate (Compound 129)

600 mg of the compound obtained in Example E10 are treated with 220 mg of 1,5-diazabicyclo [3,3,0] octane and deprotected. The title compound was obtained in an amount of 39 mg.

Example number IR spectrum (cm ' ¹ , Nujol) NMR Spectrum (δ) 155 1760.1670, 1590 _(DMSO-d6) 3.10 (6H, s), 3.4-3.7 (2H, m), 3.9-4.3 (4H, m), 5.00 (IH, d, J = 5.0 Hz), 5:05 (2H, s); 5.5-5.9 (2H, m), 7.18 (1H, d, J = 15.3 Hz), 7.56 (1H, brs), 8.18 (2H, brs), S.27 (1H, brs), 9.61 (1H, d, J = 8.3 Hz) 156 1765.1598 _(DMSO-d6) 3:00 (3H, s), 3.2-3.7 (10H, m), 3.95-4.25 (2H, m) 5.00 (2H, d, J = 4.7 Hz), 5:05 (2H, s); 5.45-5.8 (2H, m), 7.09 (2H, brs), 7.15 (1H.d, J = 15.0 Hz), 8.18 (2H, brs), 9.60 (1H, d, J = 8.2 Hz) 157 1765.1598 _(DMSO-d6) 2.75-3.3 (12H, m), 2.35-3.75 (2H, m). 3.75-4.1 (2H, m), 4.99 (1H, d, J = 4.8Hz), 5.05 (2H, s), 5.05 (2H, s), 5.35-5.8 (2H, m), 7.10 (1H, d, J = 15.5 Hz), 8.20 (2H, brs), 9.62 (1H, d, J = 8.3 Hz) 158 1760, 1670, 1595 _(DMSO-d6) 3.2-3.4 (2H, m), 4.99 (1H, d, J = 5.0 Hz). 5.10 (2H, s), 5.15-5.45 (2H, m), 5.5-6.05 (2H, m), 7.20 (1H, d, Μ5.5 Hz), 8.19 (3H, brs), 8.37 (2H, d, J = 6.0 Hz), 8.80 (1H, brs), 9.11 (2H, d, J = 6.0 Hz), 9.63 (1H, d, J = 8.0 Hz) 159 1760, 1665, 1595 _(DMSO-d6) 3:06 (6H, s), 3.35-3.65 (2H, m), 4.15 (2H, brs), 4.99 (IH, d, J = 5.2 Hz), 5:05 (2H, s), 5.4- 5.85 (2H, m), 7.15 (1H, d, J = 15.7 Hz), 8.18 (2H, brs), 9.36 (1H, s). 9.61 (1H, d, J = 8.0 Hz) 160-A 1765.1595 (DMSO-d 6) 1.95-2.35 (2H, m), 2.63 (3H, s), 3.00 (3H, s), 2.85-3.75 (6H, m), 3.85-4.35 (2H, m), 4.98 (1H, d, J = 5.1 Hz), 5.04 (2H, s), 5.25-5.75 (2H, m), 7.13 (1H, d, J = 15.5 Hz), 8.18 (2H, brs), 9.60 (1H, d, J) = 8.0 Hz) 160-B 1760.1590 (DMSO-d6) 1.95-2.35 (2H, m), 2.63 (3H, s), 3.00 (3H, s), 2.9-3.75 (6H, m), 3.85-4.35 (2H, m), 4.98 (1H, d, J = 5.0 Hz), 5.04 (2H, s), 5.3-5.75 (2H, m), 7.13 (1H, d, J = 15.5 Hz), 8.19 (2H, brs), 9.60 (1H, d, J) = 8.0 Hz) 161 1765.1600 _(DMSO-d6) 2.1-2.45 (4H, m), 2.9-3.9 (10H, m). 3.95-4.2 (2H, m), 5.04 (1H, d, J = 5.0Hz), 5.10 (2H, s), 5.5-5.8 (2H, m), 7.21 (1H, d, J = 16.0Hz), 8.30 (2H, brs), 9.70 (1H.d, J = 8.0Hz)

Eli example

2- (5-Amino-1,2,4-thiadiazol-3-yl) - (Z) -fluoromethoxyiminoacetyl chloride hydrochloride (starting compound of formula 130)

Dissolve 395 mg of phosphorus pentachloride in 2.9 ml of dichloromethane, cool to -5 ° C, add 627 mg of the compound of Example E2, stir for 2.5 hours, then add 9.4 ml of n-hexane and The resulting crystalline material was collected by filtration and washed with n-hectane to give 325 mg of the title compound. Melting point: 139-140 ° C (dec.).

Mass Spectrum (m / e): M ⁺ - 480 ( ³⁵ Cl), 482 ( ³⁷ Cl)

IR spectrum (cm ^-1 , Nujol): 1795.1780.1740.1630

NMR spectrum (δ, _DMSO-d6): 5.79 (2H, d, J = 54Hz), 7.31 (15H, s), 10.09 (IH, s).

Example E12

2- (5-Amino-1,2,4-thiadiazol-3-yl) - (Z) -2-fluoromethoxyiminoacetic acid ethyl ester (starting material of Formula 131), obtained according to Example E1. After stirring for 30 minutes at room temperature in trifluoroacetic acid, the solvent was distilled off and the residue was chromatographed on a silica gel column to give 405 mg of the title compound. Melting point: 172-173 ° C

IR (cm ^-1 , Nujol): 1730.1615

HU 207 088 Β

NMR spectrum (δ, _DMSO-d6): 1.28 (3H, t, J = 7.0 Hz);

4.34 (2H, q, J = 7.0 Hz), 5.83 (2H, d, J = 54 Hz),

8.27 (2H, brs).

Example E3 2- (5-Amino-1,2,4-thiadiazol-3-yl) - (Z) -2-fluoromethoxyimino-acetic acid (starting material of formula 132)

Example 2 (200 mg) was suspended in a mixture of ethanol (6 ml) and water (2 ml), 1N aqueous sodium hydroxide solution (1.75 ml), stirred at 60 ° C for 1 hour, and the ethanol was distilled off and the pH of the is adjusted to 2 with 1N hydrochloric acid. The resulting solution was then purified on a "Dia-Ion SP 207" (non-ionic adsorption resin, manufactured by Mitsubishi Chemical Industries, Ltd.) to give 30 mg of the title compound.

IR spectrum (cm ^-1 , Nujol). 1720, 1620

Nuclear Magnetic Resonance Spectrum (δ, DM 50 O-d ₆ ): 5.74 (2H, d, J = 55 Hz),

8.24 (2H, br).

Example EI4 p-Methoxybenzyl 7beta- [2- (5-trityl-amino-1,2,4-thiadiazol-3-yl) - (Z) -2-fluoromethoxyiminoacetamido] -3 - [( ) -3-Chloro-1-propen-1-yl / -3-cephem-4-carboxylate (starting compound of formula 133) was mixed with 5 ml of tetrahydrofuran and 15.7 ml of dichloromethane, and ethyl acetate (8.17 g) was added. N- (trimethylsilyl) acetamide and 3.33 g of p-methoxybenzyl 7-beta-amino-3 - ((Z) -3-chloro-1-propen-1-yl) -3-cephem-4-carboxylate hydrochloride, the solution is cooled to -20 ° C and 3.80 g of the compound of Example 1 are finally added and the resulting reaction mixture is stirred at 10 ° C for 1 hour. Ethyl acetate (500 mL) was added and the mixture was washed successively with water, saturated aqueous sodium bicarbonate solution, 1N hydrochloric acid, and saturated brine, dried over anhydrous magnesium sulfate, and the solvent was distilled off. The residue was chromatographed on silica gel to give 4.33 g of the title compound. The IR and NMR spectra of the material obtained were identical to those of Example E3.

El 5 Examples

2-Cyano-2-fluoromethoxyiminoacetamide (starting compound 134)

Dissolve 22.6 g of 2-cyano-2-hydroxyiminoacetamide in 100 ml of dimethylsulfoxide, add 55.2 g of potassium carbonate at room temperature with stirring and stir for a further 20 minutes. 27 g of fluorobromomethane dissolved in 20 ml of dimethylformamide are added, the mixture is stirred for 20 hours at room temperature and finally cooled. The reaction solution was then treated with 1 liter of ice water, extracted twice with 150 ml each of ethyl acetate, and the organic layer was washed twice with brine, dried over anhydrous magnesium sulfate, and the solvent was distilled off. The residue was washed with ethyl ether and dried to give 14.4 g of the title compound.

Melting point: 124-125 ° C

IR (cm ^-1 , Nujol): 3410, 3290, 3150, 1690,

1590

NMR spectrum (δ, _DMSO-d6): 5.94 (2H, d, J = 54.0

Hz), 7.85-9.40 (2H, b).

Example E16

2-Fluoromethoxyimino-propanedonitrile (starting compound 135) g of example E15 is mixed with 15 ml of acetonitrile, 15 g of sodium chloride, 14 ml of phosphoryl chloride is added and the resulting reaction mixture is refluxed for 2 hours. Phosphoryl chloride (5 mL) was then added and the reaction was continued for 2 hours. The reaction solution is then cooled, 200 ml of ice water are added and the mixture is stirred at room temperature for 1 hour. The solution was then extracted with methylene chloride (2 x 50 mL), and the extracts were washed with 5% aqueous sodium bicarbonate solution, brine and dried over magnesium sulfate. The solvent was evaporated and the oily residue was distilled off under reduced pressure to give 9.1 g of the title compound as a colorless oil.

Boiling point: 69-70 ° C / 25 mmHg

Nuclear Magnetic Resonance Spectrum (δ, CDCl ₃ ): 5.85 (2H, d, J = 52.0 Hz).

Example EI7

2-Cyano-2-fluoromethoxyiminoacetamidine (starting compound 136) was mixed with 28% aqueous ammonia solution (g) in ammonium chloride (g), ethanol (50 ml), cooled to -5 ° C and added with stirring (9.1). g of the compound obtained in Example E16 and stirring was continued for a further 3 hours. Water (100 mL) was added, the solution was extracted with methylene chloride (2 x 50 mL), the extracts were dried over anhydrous magnesium sulfate, the solvent was distilled off and the residue was washed with ethyl ether. After drying, 3.4 g of the title compound are obtained.

A portion of the above product was dissolved in ethanol and glacial acetic acid was added dropwise with stirring, and the resulting precipitate was collected by filtration, washed with ethanol and dried. The acetate salt of the title compound is thus obtained.

Melting point: 125-127 ° C

IR (cm ^-1 , Nujol): 3200, 1670, 1570 NMR (δ, DMSO-d ₆ ): 1.90 (3H, s), 5.95 (2H, d, J = 54.0 Hz). , 7.40 (3H, b).

Example EI8

2- (5-Amino-1,2,4-thiadiazol-3-yl) - (E) -2-fluoromethoxyiminoacetonitrile (starting compound 137) g of the compound obtained in Example E17 is dissolved in 50 ml of methanol. , 4.2 g of triethylamine are added, the resulting solution is cooled to -5 ° C and 3.5 g of bromine are added dropwise. A solution of 2.1 g of potassium thiocyanate in methanol is then added dropwise between -3 and -5 ° C.

EN 207 088 Β and then stir at this temperature for 2 hours. The resulting precipitate was collected by filtration, washed with water and then methanol, and the precipitate was recrystallized from acetone to give 3.4 g of the title compound.

Melting point: 236-238 ° C

IR spectrum (cm ^-1 , Nujol): 3450, 3250, 3075, 1610, 1520

NMR spectrum (δ, _DMSO-d6): 6.02 (2H, d, J = 54Hz), 8.32 (3H, b).

Chromatography gave 0.4 g of the title compound.

The infrared and NMR spectra of the above compound were identical to those of Example E13.

Example 162

Preparation of Injection Preparation The compound obtained in Example 1 (g) is dissolved in ml of distilled water and the resulting solution is poured into 5 ml vials. Finally, lyophilize.

El 9 examples

2- (5-Amino-1,2,4-thiadiazol-3-yl) - (Z) -2-fluoromethoxyiminoacetamide (starting compound 138)

0.23 g of sodium hydroxide is dissolved in 18 ml of water and 7.4 ml of 35% aqueous hydrogen peroxide are added. Thereafter, 2 g of the compound of Example E18 are added at room temperature with stirring, and the resulting solution is stirred at 25 to 30 ° C for an additional 8 hours, the precipitate is filtered off, washed with water and then with acetone and finally dried. 1.3 g of the title compound are obtained.

Melting point: 210-211 ° C

IR spectrum (cm ^-1 , Nujol): 3450, 3260, 3180, 1690,

1610

NMR spectrum (δ, _DMSO-d6): 5.73 (2H, d, J = 55 Hz);

7.69 (2H, br), 7.98 (1H, br), 8.10 (1H, br).

Example E20

2- (5-Amino-1,2,4-thiadiazol-3-yl) - (Z) -2-fluoromethoxyimino-acetic acid (starting compound 139)

1.1 g of the compound obtained in Example E19 are mixed with 10 ml of 2N aqueous sodium hydroxide solution, the resulting mixture is stirred at 50 ° C for 5 hours, and then cooled to pH 1 with concentrated hydrochloric acid. and extracted with 20 ml of ethyl acetate. The extract was dried over anhydrous magnesium sulfate and the solvent was evaporated. The residue was washed with isopropyl ether to give 0.8 g of crude product, which was reversed-phase on silica gel.

Example 163

Preparation of Injection Preparation The compound of Example 151 (g) is dissolved in 50 ml of distilled water and then filled into 5 ml vials and lyophilized.

The acute toxicity and antibacterial activity of the compounds of the present invention were determined as follows:

1. Measurement of acute toxicity in mice

The compounds of the present invention are dissolved in physiological saline and administered intravenously to 5 ICR 6 week old male mice. Based on the results obtained, the following examples showed acute toxicity above 2 g / kg: 1, 2-1, 2-2, 3-1,

3-2, 5, 6-1, 6-2, 7-1, 7-2, 9-1, 9-2, 9-3, 10, 11, 12, 13-1, 13-2.96, 121, 137, 145, 146, 150, 151, 154 and 155.

2. Antibacterial activity (MIC)

MIC values (gg / ml) were determined by the agar dilution method (Chemotherapy (Japan), 29, 76-79, 1981). It was diluted to 10 ⁶ CFU / ml and 5 μΐ of each bacterial suspension was inoculated with a Mueller-Hinton agar plate containing twice diluted antibiotic compound. MIC values were determined after incubation for 18 hours at 37 ° C.

Known compounds CAZ (cefetazidime) and CTM (cefotiam) were used as controls.

Bacteria tested MIC (gg / ml) Test compound Slaph. aurelius 209-P Escher. coli NIHJ Klebsiella. pneumoniae EK-6 Ser. Marcescens ES-75 Morganella morganii EP-14 Pseud. aeruginosa EP-0I 1 0.2 <0025 <0025 0.1 <0025 0.8 2-1 0.4 0:05 0:05 0:05 0:05 1:56 2-2 0.4 <0025 <0025 <0025 <0025 1:56 3-1 0.2 <0025 <0025 0:05 <0025 0.8 3-2 0.2 <0025 <0025 0.1 <0025 1:56 4 0.4 0:05 <0025 0.1 0:05 0.8 5 0.2 <0025 <0025 <0025 <0025 0.8 6-1 0.2 0:05 <0025 <0025 <0025 0.8 6-2 0.1 <0025 <0025 <0025 <0025 0.8 7-1 0.2 <0025 <0025 <0025 <0025 0.8

HU 207 088 Β

Bacteria tested MIC (g / ml) Test compound Staph. aurclius 209-1 ' Escher. coli NIHJ Klebsiella. pneumoniae EK-6 Ser. Marcescens ES-75 Morganella morganii EP-14 Pseud. aeruginosa EP-01 7-2 0.2 <0025 <0025 <0025 <0025 0.8 ⁸ 0.2 <0025 <0025 <0025 <0025 0.8 9-1 0.4 <0025 <0025 <0025 <0025 0.8 9-2 0.4 <0025 <0025 <0025 <0025 0.8 9-3 0.4 <0025 <0025 <0025 <0025 0.8 10 0.8 <0025 <0025 <0025 <0025 1:56 Π 0.4 <0025 <0025 <0025 <0025 0.8 12 0.4 0:05 <0025 0.1 0:05 1:56 13-1 0.2 <0025 <0025 <0025 <0025 0.8 13-2 0.2 <0025 <0025 0:05 0:05 1:56 14 0.2 <0025 <0025 0:05 <0025 0.8 15-1 0.4 0:05 <0025 <0025 <0025 1:56 15-2 0.4 <0025 <0025 <0025 <0025 1:56 16 0.2 <0025 <0025 <0025 <0025 0.8 17 0.4 <0025 <0025 <0025 <0025 0.8 19 0.2 <0025 <0025 0:05 <0025 0.8 20 0.2 <0025 <0025 0:05 <0025 1:56 21 0.2 <0025 <0025 0.1 <0025 1:56 22 0.2 0:05 0:05 0.2 0:05 3:13 23 0.2 <0025 <0025 <0025 <0025 1:56 23-2 0.2 0:05 <0025 <0025 0:05 1:56 24 0.2 <0025 <0025 <0025 <0025 1:56 26 0.2 0.1 0.1 0.4 0.1 0.8 27 0.4 0:05 <0025 0.1 0:05 1:56 28 0.4 0:05 0:05 0.2 0:05 1:56 29 0.4 <0025 <0025 0.1 <0025 0.8 30 0.4 0:05 0:05 0.2 0:05 1:56 31 0.4 0:05 <0025 0.1 <0025 1:56 32 0.2 <0025 <0025 0:05 <0025 1:56 35 0.4 0:05 <0025 0.1 0:05 0.8 36 0.2 0:05 <0025 0.1 0:05 1:56 37 0.2 0:05 <0025 0.1 0:05 1:56 38 0.4 0.1 0:05 0.2 0.1 1:56 39 0.2 0:05 <0025 0.1 0:05 1:56 40 0.4 <0025 <0025 <0025 <0025 0.8 42 0.2 <0025 0:05 <0025 <0025 1:56 43 0.2 <0025 <0025 <0025 <0025 0.8 44 0.4 0:05 <0025 0.1 0:05 1:56 45 0.4 <0025 <0025 0.1 <0025 0.8 50 0.4 0:05 0:05 0.2 0:05 1:56 51 0.4 0:05 0:05 0:05 0:05 1:56 53 0.8 0:05 0:05 0.1 0:05 0.8 55 0.2 <0025 <0025 <0025 <0025 0.4 '

HU 207 088 B

Bacteria tested MIC (gg / ml) Test compound Staph. aurelius 209-P Escher. coli NIHJ Klebsiella. pneumoniae EK-6 Ser. Marcescens ES-75 Morganella morganiiEP-14 Pseud. aeruginosa EP-01 56 0.4 0:05 0:05 0.1 0:05 1:56 57 0.2 0:05 0:05 0.2 <0025 0.8 58 0.2 <0025 0:05 0:05 0:05 1:56 59 0.4 <0025 <0025 <0025 <0025 1:56 60 0-2 <0025 0:05 <0025 <0025 1:56 61 0.4 0.1 0:05 0:05 0.1 1:56 62 0.2 <0025 <0025 <0025 <0025 0.4 63 0.4 <0025 0:05 <0025 <0025 0.8 64 0.2 <0025 <0025 0.1 <0025 0.8 65 0.4 <0025 <0025 0:05 <0025 0.8 66 0.4 <0025 <0025 <0025 <0025 0.8 67 0.1 <0025 <0025 <0025 <0025 0.8 68 0.2 <0025 <0025 <0025 <0025 0.8 69 0.2 <0025 <0025 0:05 <0025 0.8 70 0.1 <0025 <0025 0.1 <0025 0.8 72 0.4 <0025 <0025 <0025 <0025 0.8 73 0.4 0:05 0:05 0:05 0.1 1:56 74 0.8 0.1 0:05 0.4 0.1 1:56 75 0.4 0:05 0:05 0.2 0:05 1:56 77 0.4 0.2 0.2 0.2 0.4 3:13 78 0.4 0.2 0.2 0.2 0.2 3.13. 81 0.2 <0025 <0025 <0025 <0025 1:56 82 0.4 <0025 <0025 0:05 <0025 1:56 83 0.8 0:05 <0025 0.1 <0025 3:13 84 0.4 0:05 <0025 0.1 0:05 1:56 85 0.2 <0025 <0025 <0025 <0025 1:56 88 0.2 <0025 <0025 <0025 <0025 0.8 89-1 0.2 <0025 <0025 <0025 <0025 0.8 89-2 0.2 <0025 <0025 <0025 <0025 0.8 90 0.2 0:05 <0025 <0025 0:05 0.8 91 0.2 0:05 <0025 <0025 <0025 1:56 92 0.2 <0025 <0025 <0025 <0025 0.8 93 0.2 <0025 <0025 <0025 <0025 0.8 94 0.2 <0025 <0025 <0025 <0025 0.8 95 0.2 0:05 <0025 <0025 <0025 0.8 96 0.2 <0025 <0025 <0025 <0025 0.8 97 0.2 <0025 <0025 <0025 <0025 0.8 98 0.4 0:05 0:05 0:05 <0025 3:13 99 0.2 <0025 <0025 <0025 <0025 1:56 100 0.2 <0025 <0025 0:05 <0025 1:56 101 0.2 0:05 <0025 <0025 <0025 1:56 102 0.2 <0025 <0025 0:05 <0025 1:56 103 0.1 <0025 <0025 <0025 <0025 3:13

HU 207 088 B

Bacteria tested MIC (gg / ml) Test compound Staph. aurelius 209-P Escher. coli NIHJ Klebsiella. pneumoniae EK-6 Ser. Marccsccns ES-75 Morganella morganii EP-14 Pseud. aeruginosa EP-OI 106 0.4 <0025 0:05 0.1 0:05 3:13 107 0.2 0:05 <0025 0:05 <0025 1:56 108 0.4 0:05 <0025 0.1 0:05 3:13 114 0.2 0:05 <0025 0:05 <0025 0.8 115 0.8 <0025 <0025 0:05 <0025 3:13 116 0.2 <0025 <0025 <0025 <0025 1:56 117 0.4 0:05 0:05 0.2 <0025 1:56 118 0.2 <0025 <0025 0.1 <0025 0.4 119 0.2 <0025 <0025 0:05 <0025 0.8 120 0.2 <0025 <0025 0:05 <0025 0.8 121 0.2 <0025 <0025 0.1 <0025 0.8 122-A 0.2 <0025 <0025 <0025 <0025 0.8 122-B 0.1 <0025 <0025 0:05 <0025 0.8 123 0.4 0:05 0:05 0.2 0:05 1:56 124 0.2 0:05 <0025 0.1 0:05 0.8 125 0.4 <0025 <0025 <0025 <0025 1:56 126 0.1 <0025 <0025 0:05 <0025 0.8 127 0-1 <0025 <0025 0:05 <0025 0.8 128 0.2 0:05 0:05 0.1 0:05 0.8 129 0.2 <0025 <0025 0:05 <0025 0.8 143 0.2 0:05 <0025 0.1 <0025 0.8 144 0.2 <0025 0:05 0.1 <0025 0.8 145 0.4 0.2 0.1 0.1 0.1 1:56 146 0.4 0.1 0:05 0:05 0:05 1:56 147 0.2 0.1 0:05 0.2 0:05 1:56 148 0.4 0.1 0:05 0:05 0.1 1:56 149 0.2 0.1 0:05 0:05 0:05 1:56 150 0.4 0.2 0.1 0.1 0.1 1:56 151 0.4 0.1 0:05 0:05 0:05 1:56 152 0.2 0.1 0:05 0:05 0:05 1:56 153 0.4 0.2 0.1 0.1 0.1 1:56 154 0.4 0.1 0.1 0.1 0.1 0.8 155 0.4 0.1 0:05 0.2 0.1 1:56 156 0.4 0.1 0.1 0.1 0.1 0.8 ¹⁵⁷ 0.4 0.1 0.1 0.2 0.1 1:56 158 0.2 <0025 <0025 0.1 0.1 1:56 159 0.4 0:05 0:05 0.1 MCD 1:56 160-A 0.1 <0025 <0025 0.1 0:05 0.8 160-B 0.1 0:05 0:05 0.2 0:05 0.8 161 0.2 0:05 0:05 0.2 0.1 1:56 CAZ 6:25 0.2 0.1 0.2 0.1 1:56 CTM 0.2 0.1 0.1 6:25 > 100 0.2

HU 207 088 Β

3. Antibacterial activity (MIC)

A comparative study of the antibacterial activity between the compound of formula 140 and a control compound in which R1 represents a methyl group was performed. Measurements were performed as described in the previous section. The results are summarized in the following table.

THE R. MIC (µg / ml) Bacteria tested Staph. aureus E3II06 Enterobacter cloacae, E-74 Proteus vulgaris E 08042 Xantomonas mallophilia E 04004 141 -CH, F (Example 126) 1:56 0:05 0:05 12.5 -CH ₃ (control) 6:25 0.1 1:56 100 142 -CH ₂ F (Example 127) 3:13 <0025 <0025 6:25 -CH ₃ (control) 6:25 0.4 3:13 50 Compound 143 -CH ₂ F (Example 125) 6:25 0.4 0.2 25 -CH ₃ (control) 12.5 3:13 12.5 50 144 -CH ₂ F (Example 128) 3:13 0.1 0.1 25 -CH ₃ (control) 6:25 0.2 6:25 > 100

PATENT CLAIMS

Claims (5)

PATENT CLAIMS A process for the preparation of the 3-propenyl cephem derivatives of the formula I and their salts wherein R 1 is fluoro-lower alkyl or cyano-lower alkyl; A is a group of Formula (a ') wherein: R ₂ , R ₃ and R ₄ are each independently lower alkyl, hydroxy lower alkyl, carbamoyl lower alkyl, amino, (lower alkyl) carbonylamino-lower alkyl, amino -sulfonylaminocarbonyl-lower alkyl, (lower alkyl) sulfonylaminocarbonyl-lower alkyl, (lower alkyl) aminocarbonyl-lower alkyl, (hydroxyl) - (carbonyl) - lower alkyl, hydroxyl, and hydroxy (lower alkyl) aminocarbonyl lower alkyl, (lower alkyloxyaminocarbonyl) lower alkyl, hydroxyaminocarbonyl lower alkyl- , aminocarbonyl (lower alkyl) aminocarbonyl-lower alkyl, [(lower alkyl) amino-lower alkyl], cyano-lower alkyl, carboxylate (lower alkyl) -di- ( lower alkylammonio-short s lower alkyl, di- (lower alkyl) amino-lower alkyl, [(lower alkyl) amino], and hydroxyl lower alkyl, urea, hydroxyl, carboxyl lower alkyl -, (hydroxyl) (carbamoyl) lower alkyl, lower alkyloxy lower alkyl, di (lower alkyl) aminocarbonyl lower alkyl, dicarbamoyl lower alkyl, bis / hydroxy, lower alkyl) / aminocarbonyl lower alkyl, dihydroxy lower alkyl, trihydroxy lower alkyl, bis / hydroxy (lower alkyl) amino-lower alkyl, amino lower alkyl- , oxo-lower alkyl, di-lower alkylamino-lower alkyl, 5-membered heterocyclic lower alkyl, wherein the heterocyclic group is pyrazolyl-imidazolyl, oxadiazolyl or tetrazolyl; A may also be represented by the general formula (a) - (r) in which _R5 is lower alkyl, carbamoyl-lower alkyl, amino-lower alkyl, hydroxy-lower alkyl, karboxilrövid lower alkyl, cyano-lower alkyl, dihydroxy-lower alkyl, or ureido lower alkyl and the above groups (a) - (r) may be substituted on the ring with one or more of the following groups: hydroxy-lower alkyl, hydroxyl, boiling, sulfone, carboxyl-lower alkyl, carbamoyl, sulfamoyl, carboxyl, hydroxyimino-lower alkyl, imino-lower alkyl, bis / hydroxy (lower alkyl) / aminocarbonyl, hydroxy (lower alkyl) aminocarbonyl- , amino, morpholinocarbonyl, carboxy (lower alkyloxy) lower alkyl, carboxy (lower alkyl thio), lower alkyl, and sulfone lower alkyl, characterized in that wherein R 1 is as defined above and X is 45 Or a salt or a protected form of its chemical or amino and / or carboxylic acid with a compound of formula (III) wherein A 'is an amino group corresponding to A above - or a protected form or salt of this compound. and optionally deprotecting and converting the resulting compound to a pharmaceutically acceptable salt thereof. (Priority: October 12, 1987) 2. A process for the preparation of the 3-propenyl cephem derivatives of the general formula (1) and their salts R 1 is cyano-lower alkyl, A is a group of formula (a ') wherein R ₂ , R ₃ and R ₄ are independently lower alkyl, hydroxide lower alkyl, carbamoyl lower alkyl, οχο lower alkyl, and A may also be a group of formula (a) wherein _R5 is lower alkyl and the (a) group of the formula may be substituted on the ring by one or more of the radicals of hydroxy or hydroxy-lower alkyl, wherein the (II) compound of the formula: - wherein R is as above and X is a halogen atom, or a salt or a protected form of its compound and its amino and / or carboxylic acid is reacted with a compound of the formula III, wherein A 'is an amino group corresponding to A above, or a protected form or salt thereof; optionally deprotecting and converting the resulting compound to a pharmaceutically acceptable salt thereof. (Priority: September 7, 1987) 3. A process for the preparation of the 3-propenyl cephem derivatives of the formula (I) and their salts R 1 is fluoro-lower alkyl, A is a group of formula (a ') wherein R ₂ , R ₃ and R ₄ are each independently lower alkyl, hydroxide lower alkyl, carbamoyl lower alkyl, amino, (lower alkyl) carbonylamino-lower alkyl, amino -sulfonylaminocarbonyl-lower alkyl, (lower alkyl) -sulfonylaminocarbonyl-lower alkyl, (lower-alkyl) -aminocarbonyl-lower alkyl, (hydroxyl) -carbonyl-lower alkyl- , (hydroxy) hydroxy (lower alkyl) aminocarbonyl lower alkyl, (lower alkyloxy) aminocarbonyl lower alkyl, hydroxyaminocarbonyl lower alkyl, amino -carbonyl (lower alkyl) -aminocarbonyl-lower alkyl, hydroxy (lower alkyl) -aminocarbonyl lower alkyl, (lower alkyl) amino, lower alkyl, cyano lower alkyl, carboxylate (short chain alkyl-di- (lower-alkyl) -amino-lower-alkyl, di (lower-alkyl) -amino-lower-alkyl, [(lower-alkyl) -amino] - (hydroxyl)-lower alkyl- , urea, hydroxyl, carboxy-lower alkyl, (hydroxy) (carbamoyl) -alkyl, lower-alkyloxy-lower alkyl, di (lower-alkyl) -aminocarbonyl-lower alkyl -, dicarbamoyl-lower alkyl, bis / hydroxy-lower alkyl / aminocarbonyl-lower alkyl, di-hydroxy-lower alkyl, trihydroxy-lower alkyl, bis / hydroxy (lower alkyl) amino- lower alkyl, 5-membered heterocyclic lower alkyl wherein the heterocyclic group is oxadiazolyl or tetrazolyl; A may also be represented by the formula (a) - (m) wherein _R5 is lower alkyl, carbamoyl-lower alkyl, amino-lower alkyl, hydroxy-lower alkyl, karboxilrövid lower alkyl, cyano-lower alkyl, dihydroxy-lower alkyl, or ureido lower alkyl, and the above groups (a) to (m) may be further substituted on the ring with one or more of the following groups: hydroxy-lower alkyl, hydroxyl, formylsulfone, carboxyl-lower alkyl, carbamoyl, sulfamoyl, carboxyl, hydroxyimino-lower alkyl, imino-lower alkyl, bis / hydroxy (short) lower alkyl) / aminocarbamoyl, hydroxy (lower alkyl) aminocarbamoyl, aminomorpholinocarbonyl, carboxy (lower alkyloxy) lower alkyl, carboxy (lower alkyl thio) characterized in that a compound of the formula II in which R 1 is as defined above and X is a halogen atom or a salt or a protected form of its amino and / or carboxyl group with a compound of the formula III A 'is reacted with a protected form or salt of an amino group corresponding to Group A above, optionally deprotected and converted to the pharmaceutically acceptable salt thereof. k. Priority: September 3, 1987 A process for the preparation of the 3-propenyl cephem derivatives of the formula I and their salts wherein R 1 is a fluoro lower alkyl group A is a group of the formula (a '), wherein R ₂ and R j are hydroxy lower alkyl, R ₄ is lower alkyl or hydroxyl lower alkyl, characterized in that a ve46 of formula II A compound B wherein R 1 is as defined above and X is halogen or a salt or protected form thereof of the compound and its amino and / or carboxyl group with a compound of formula III wherein A 'is an amino group corresponding to A above. or with a protected ton or salt of this compound, optionally deprotecting and converting the resulting compound to a pharmaceutically acceptable salt thereof. Priority: February 3, 1987 5. A process for the preparation of 3-propenyl cephem derivatives of the formula (I) and their salts R | is fluoro-lower alkyl, A is a group of formula (a ') wherein R ₂ and R ₃ are lower alkyl, and R ₄ is lower alkyl, amino, carbamoyl lower alkyl, hydroxyl lower alkyl, amino lower alkyl, di (lower alkyl) - amino-lower alkyl, 5-membered heterocyclic-lower alkyl wherein the heterocyclyl is pyrazolyl, imidazolyl, oxadiazolyl or tetrazolyl; A may also be a, b, c, d, f, j, 1, m-q, wherein _R5 represents a lower alkyl group, and said cyclic group may be substituted one or more selected from the group of the ring with lower alkyl, hydroxy-lower alkyl, carboxy, carboxy-lower alkyl, carbamoyl, imino a lower alkyl, sulfamoyl, or sulfone moiety characterized in that a compound of formula II wherein R 1 is as defined above and X is halogen, or a salt or amino protected form thereof and a carboxyl protected form thereof, The compound of formula III, wherein A 'is an amino group corresponding to group A above, or a protected form or salt thereof, is optionally deprotected and converted to the pharmaceutically acceptable salt thereof. Priority: November 6, 1986 6. A process for the preparation of 3-propenyl cephem derivatives of the formula (I) and their salts R | is a cyano-lower alkyl group A is a group of the formula (a '), wherein R ₂ and R ₃ represents lower alkyl, R ₄ is lower alkyl, amino, carbamoyl lower alkyl, 5-membered heterocyclic-lower alkyl wherein the heterocyclic group is pyrazolyl, oxadiazolyl, imidazolyl or tetrazolyl; A may also be a, b, d, f, j, 1, n, o, p, r wherein R _s is lower alkyl and the foregoing groups may be additionally substituted on the ring by one or more of the following groups: hydroxy, lower alkyl, carboxy. carbamoyl, lower alkyl, sulfamoyl, or imino lower alkyl, characterized in that a compound of the formula (II) in which R 1 is hydrogen; is as defined above, and X is a halogen atom, or a salt or a protected form thereof, of an amino and / or carboxyl group thereof, with a compound of formula III, wherein A 'is an amino group corresponding to the above group A, and deprotecting and converting the resulting compound to a pharmaceutically acceptable salt thereof. Priority: October 13, 1986 7. A process for the preparation of a pharmaceutical composition, which comprises as an active ingredient a 3-propenyl cephem derivative of the formula I as claimed in claim 1 or a pharmaceutically acceptable salt thereof, wherein R and A are as defined in claim 1 with a pharmaceutically acceptable carrier and / or mixed with excipients and formulated for administration as a dosage form. Priority: October 12, 1987 8. A process for the preparation of a pharmaceutical composition, which comprises as an active ingredient a 3-propenyl cephem derivative of the formula I according to claim 2 or a pharmaceutically acceptable salt thereof, wherein R and A are as defined in claim 1, with an acceptable air carrier and / or mixed with excipients and formulated for administration as a dosage form. Priority: September 7, 1987 9. A process for the preparation of a pharmaceutical composition, which comprises as an active ingredient a 3-propenyl cephem derivative of the formula I as claimed in claim 3 or a pharmaceutically acceptable salt thereof, wherein R and A are as defined in claim 1 with a pharmaceutically acceptable carrier and / or mixed with excipients and formulated for administration as a dosage form. Priority: September 3, 1987 10. A process for the preparation of a pharmaceutical composition, which comprises as an active ingredient a 3-propenyl cephem derivative of the formula I according to claim 4 or a pharmaceutically acceptable salt thereof, wherein R 1 and A are as defined in claim 1, and a pharmaceutically acceptable carrier. / or mixed with excipients and formulated for administration as a dosage form. Priority: February 3, 1987 11. A process for the preparation of a pharmaceutical composition comprising a 3-propenyl cephem derivative of the formula I as claimed in claim 5 or a pharmaceutically acceptable salt thereof, wherein R 1 and A is mixed with a pharmaceutically acceptable carrier and / or excipient according to claim 1 and formulated into a pharmaceutical composition for administration. Priority: November 6, 1986 HU 207 088 Β 12. A process for the preparation of a pharmaceutical composition, wherein the active ingredient is a 3-propenyl cephem derivative of the Formula I or a pharmaceutically acceptable salt thereof according to claim 6, wherein R and A are as defined in claim 1. A pharmaceutical composition according to claim 1 which is admixed with a pharmaceutically acceptable carrier and / or excipient and is formulated to be administered. 5 Priority; October 13, 1986